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Microbiology and Molecular Biology Reviews, December 2008, p. 590-641, Vol. 72, No. 4
1092-2172/08/$08.00+0 doi:10.1128/MMBR.00016-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas
Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland 21205-2185
SUMMARY INTRODUCTION PEPTIDE INHIBITORS alpha-Helical Basic Peptide Inhibitors Angiostatin and Enterostatin Tentoxin and Its Derivatives Leucinostatins and Efrapeptins POLYPHENOLIC PHYTOCHEMICALS, ESTROGENS, AND STRUCTURALLY RELATED COMPOUNDS Stilbenes Flavones and Isoflavones Other Polyphenolic Phytochemicals Steroidal Estradiols and Estrogen Metabolites POLYKETIDE INHIBITORS ORGANOTIN COMPOUNDS AND STRUCTURAL RELATIVES POLYENIC alpha-PYRONE DERIVATIVES CATIONIC INHIBITORS Amphiphilic Cationic Dyes TALAs and Related Compounds Other Organic Cations SUBSTRATES AND SUBSTRATE ANALOGS Phosphate Analogs Divalent Metal Ions Purine Nucleotides and Nucleotide Analogs AMINO ACID MODIFIERS Amino Group Modifiers Carboxyl Group Modifiers Cys and Tyr Residue Modifiers His Residue Modifiers Others PHYSICAL INHIBITORY FACTORS High Hydrostatic Pressure UV Irradiation Low Temperature MISCELLANEOUS INHIBITORS CONCLUSIONS ACKNOWLEDGMENTS REFERENCES
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Summary: ATP synthase, a double-motor enzyme, plays various roles in the cell, participating not only in ATP synthesis but in ATP hydrolysis-dependent processes and in the regulation of a proton gradient across some membrane-dependent systems. Recent studies of ATP synthase as a potential molecular target for the treatment of some human diseases have displayed promising results, and this enzyme is now emerging as an attractive molecular target for the development of new therapies for a variety of diseases. Significantly, ATP synthase, because of its complex structure, is inhibited by a number of different inhibitors and provides diverse possibilities in the development of new ATP synthase-directed agents. In this review, we classify over 250 natural and synthetic inhibitors of ATP synthase reported to date and present their inhibitory sites and their known or proposed modes of action. The rich source of ATP synthase inhibitors and their known or purported sites of action presented in this review should provide valuable insights into their applications as potential scaffolds for new therapeutics for human and animal diseases as well as for the discovery of new pesticides and herbicides to help protect the world's food supply. Finally, as ATP synthase is now known to consist of two unique nanomotors involved in making ATP from ADP and Pi, the information provided in this review may greatly assist those investigators entering the emerging field of nanotechnology.
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ATP synthase (F0F1) is a multisubunit, membrane-associated protein complex that catalyzes the phosphorylation of ADP to ATP at the expense of a proton motive force generated by an electron transport chain in energy-transducing membranes (303, 387). In some organisms, it also works in the reverse direction by hydrolyzing ATP and generating an electrochemical proton gradient across a membrane to support locomotion or nutrient uptake. ATP synthase is present in all living organisms and is located in the membranes of mitochondria, bacteria, and chloroplast thylakoids as well as on the surfaces of various cell types, including endothelial cells (269, 270), keratinocytes (58), and adipocytes (206).
ATP synthase is an exceptionally complicated protein complex. It is divided into two sectors, a soluble globular F1 catalytic sector and a membrane-bound F0 proton-translocating sector (Fig. 1) (304, 305). Even the simplest form of ATP synthase, found in nonphotosynthetic eubacteria, contains eight different subunit types, while the chloroplast and photosynthetic bacterial ATP synthase each consists of nine different subunit types (42, 331). The ATP synthase from mitochondria is much more complicated and, excluding regulators, is reported to date to consist of 15 and 17 different subunit types in animals and yeasts (or fungi), respectively (305, 413).
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FIG. 1. Current view of the structure of mitochondrial ATP synthase from metazoans. F1 is composed of  , β,  ,  , and  subunits, and F0 consists of a, b, c, d, e, f, g, A6L, and OSCP. IF1 is a regulatory protein. The coordinates of the subunits used in the structural model are 1E79 for the , β, , , and subunits; 1ABV for the N-terminal domain of OSCP; 2CLY for F6, d, and the hydrophilic part of the b subunit; 1GMJ for IF1; and 1B9U for the transmembrane part of the b subunit. The ac10 subcomplex was modeled using the coordinates of the a and c subunits from 1C17, and the other subunits in the model were constructed manually using Quanta. No positions are assigned to the factor B and the e subunit. Here and where indicated in the other figure legends, the coordinates of protein structures were obtained from the PDB.
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subunit are detected in Alzheimer's disease, and the intraneuronal cytosolic accumulation of the subunit is implicated in the neurodegenerative process (73, 208, 367). Moreover, the ATP synthase on the cell surface of endothelial cells has been reported to have an important role in the angiogenesis process required for tumor growth (269-271, 422). Additionally, the ATP synthase F6 subunit circulating in the blood has been recognized to be involved in the increase of blood pressure (293, 294). Finally, the β subunit of ATP synthase has been identified as a target protein for innate antitumor cytotoxicity mediated by natural killer and interleukin 2-activated killer cells (91). ATP synthase has also been demonstrated and suggested as a good molecular target for drugs in the treatment of various diseases and the regulation of energy metabolism (16, 38, 72, 193, 202, 367). One of the drugs developed for the treatment of tuberculosis, R207910, was shown to be active against a number of drug-resistant strains of Mycobacterium tuberculosis and to eradicate M. tuberculosis infection rapidly and effectively (15, 313, 340). The drug has been revealed to block the synthesis of ATP by targeting subunit c of ATP synthase. Another drug, Bz-423, which was developed for therapy of the autoimmune disorder systemic lupus erythematosus, kills pathogenic lymphocytes selectively by inducing apoptosis in lymphoid cells (41). Significantly, Bz-423 has been found to inhibit the mitochondrial ATP synthase by binding to the subunit known as oligomycin sensitivity-conferring protein (OSCP) (193). In addition, the inhibition of nonmitochondrial ATP synthase resulted in the inhibition of cytosolic lipid droplet accumulation, suggesting ATP synthase as a molecular target for antiobesity drugs (16). Finally, the inhibition of ATP synthase has been suggested for an antiangiogenic therapeutic strategy to block tumor angiogenesis (17, 59, 269-271, 422). Here, the reaction of ATP synthase inhibitors with the nonmitochondrial ATP synthase of endothelial cells has been shown to inhibit markedly the migration and proliferation of endothelial cells with little effect on intracellular ATP (17).
The aim of this review is to provide insight and encouragement into the development of new ATP synthase-directed agents. We have meticulously categorized most of the natural and synthetic inhibitors of ATP synthase reported to date in accordance with physical/chemical characteristics of the inhibitors and have summarized the current knowledge of the modes of action of these inhibitors. The information provided in this review should prove to be an invaluable resource, not only for obtaining information about the interactions of known effectors, primarily inhibitors of ATP synthase, but for generating new ideas for the development of numerous additional ATP synthase-directed agents that can be used (i) in the treatment of human and animal diseases, (ii) in agriculture as pesticides or herbicides, and (iii) in the developing field of nanotechnology to understand the mechanics of nanomotor function.
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-Helical Basic Peptide InhibitorsThe
-helical basic peptide inhibitors bind to F1 and inhibit ATPase activity (Table 1). Inhibitors in this group include -helical structures containing basic residues, which appear to be crucial for their inhibitory activities. The -helical basic peptide inhibitors include the bacterial/chloroplast subunit, melittin, the presequence of yeast cytochrome oxidase subunit IV (WT and its synthetic derivatives), and possibly the inhibitor protein (IF1) (Fig. 2A). |
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TABLE 1. -Helical basic peptide inhibitors
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FIG. 2. Structures of peptide inhibitors. (A) -Helical basic peptide inhibitors. The coordinates of the inhibitors are 1BSN for the bacterial/chloroplast subunit, 1GMJ for IF1, and 2MLT for melittin. (B) Angiostatin and enterostatin. The coordinate for the structure is 1KI0. (C) Tentoxin and tentoxin analogs. (D) Leucinostatins and efrapeptins.
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subunit, composed of 
120 to 140 amino acid residues, is an endogenous inhibitory subunit in F1, and inhibits ATPase activities of isolated and membrane-bound bacterial F1 (BF1) and chloroplast F1 (CF1) (198, 284, 332, 372, 386). The inhibition is reversible and noncompetitive with substrates (372, 386). It has no inhibitory effect on ATP synthesis and is required in the chloroplast ATP synthase for ATP synthesis in the light (289, 389, 402). The inhibition of F1-ATPase by the subunit is controlled by the electrochemical gradient and ADP/ATP balance (389), and the C-terminal -helical domain is responsible for its inhibitory activity (168, 212, 289). At high proton motive forces and low ATP concentrations, the C-terminal -helical domain of the subunit performs large conformational changes from the hairpin conformation to a "lifted-up" extended conformation, shifting its position 70 Å to interact with the 3β3 hexagon ring (389, 402). In the "lifted-up" extended conformation, the C-terminal helix lies close to the β-DELSEED motif of the β subunit, and the direct electrostatic interaction between the β-DELSEED motif and the basic residues in the C-terminal domain of the subunit leads to the inhibition of ATP hydrolysis (168).
IF1 is a natural regulatory peptide of 56 to 87 residues found in mitochondria (Fig. 2A). It binds to F1 with a 1:1 stoichiometric ratio and inhibits the ATP hydrolysis of mitochondrial ATP synthase without affecting ATP synthesis. The inhibition is reversible and noncompetitive, and the binding of IF1 to F1 requires the presence of ATP (178, 228, 229, 409). IF1 is more potent against the whole membrane-bound ATP synthase (F0F1-ATPase) complex than isolated F1 (144, 409, 411). IF1 inhibits the ATPase activity of mitochondrial ATP synthase and has no ATPase inhibitory effect against BF1 (143). The yeast IF1 can cross-react with animal F1, whereas the potato IF1 shows no inhibitory effect against animal F1 (60, 319). IF1 proteins from animals are considerably (18 to 31 residues) longer than those from plants and fungi (176). In a study of truncated bovine IF1 for inhibitory activity, the minimal inhibitory sequence was shown to localize within residues 14 to 47 (411). The adjoining residues 10 to 13 and 48 to 56 are considered to play a stabilizing role. In the crystal structure of F1 with IF1, the N-terminal domain of IF1 is bound at the interface between DP and βDP subunits and also has contacts with βTP386, E355, and the subunit (61). It has been suggested that the inhibitory mode of action of IF1 could be similar to that of the bacterial subunit (260, 402). IF1 is considered to play its inhibitory role by impeding the closure of the DP-βDP catalytic interface to prevent the hydrolysis of bound ATP (61, 141). Cross-linking and intrinsic phosphorescence decay studies implicate IF1 as being functionally associated with the mitochondrial subunit (260, 373). Both proteins are in close proximity in the crystal structure of the F1-IF1 complex (141).
Melittin, which is a 26-residue peptide known as the principal active component of bee venom and which has a powerful anti-inflammatory effect, inhibits the ATPase activity of F1 (52, 143). The 25-residue presequence of yeast cytochrome oxidase subunit IV (WT) and its synthetic derivatives, Syn-A2, Syn-C, and 
11,12, also inhibit ATP hydrolysis by F1 (52, 143). Melittin, WT, Syn-A2, and Syn-C (and possibly 11,12) form basic and amphiphilic -helical structures (191, 337, 338, 393). Melittin, Syn-A2, and Syn-C have been suggested to bind to F1 at the same site as IF1 (143), and WT and 11,12, which are derivatives of Syn-A2 and Syn-C, are considered to also play similar inhibitory roles. Syn-A2 and Syn-C are very effective inhibitors among amphiphilic peptide inhibitors, showing 50% inhibitory (I50) values of about 40 to 50 nM for inhibition of bovine F1-ATPase activity (52). Syn-A2 inhibits the ATPase activity of bovine F1 noncompetitively in a parabolic manner, whereas Syn-C exhibits mixed inhibition and melittin shows noncompetitive hyperbolic inhibition (52).
Angiostatin is a 57-kDa N-terminal fragment of a larger protein, plasmin, which is also a fragment of plasminogen. Angiostatin has a triangular structure with three to five contiguous kringle domains, and it acts as a natural angiogenesis inhibitor (Fig. 2B) (1). It binds to the
and β subunits of ATP synthase and inhibits its ATP hydrolysis (269, 270). In an experiment with bovine F1 and human angiostatin, the angiostatin bound strongly to F1 and completely inhibited ATPase activity (269). Angiostatin was also found to inhibit ATP generation by the nonmitochondrial ATP synthase located on endothelial cells that comprise the human umbilical vein, with 1 µM angiostatin inhibiting about 81% of the ATP synthesis activity (270). However, no ATP synthesis by plasma membrane ATP synthase was reported in human vascular endothelial cells (325), and the inhibition of ATP synthesis of nonmitochondrial ATP synthase by ATP synthase-specific inhibitors is still controversial.
Enterostatin is a pentapeptide released from procolipase during dietary fat digestion (Fig. 2B). Enterostatin binds to the ATP synthase β subunit and inhibits ATP synthesis (38, 39, 301). Binding of enterostatin to the mitochondrial ATP synthase in insulinoma cells leads to an 31% decrease of ATP production accompanied by an increase in thermogenesis and oxygen consumption (38). The binding of enterostatin to F1 is inhibited by β-casomorphin, a peptide derived from the digestion of β-casein in milk (38, 39, 301).
The properties and inhibitory potencies of tentoxin and its analogs are summarized in Table 2. Tentoxin is a natural cyclic tetrapeptide produced by phytopathogenic fungi, Alternaria species (19, 257, 342). In aqueous solution, tentoxin exists as four interconverting conformations in different proportions (51, 37, 8, and 4%) resulting from a "conformational peptide flip" (318). At low concentrations, tentoxin acts as an uncompetitive inhibitor of the ATPase activity of CF1 derived from certain sensitive plant species but not of homologous CF1s from chloroplasts of some other plant species. Also, tentoxin does not inhibit the ATPase activity of F1s derived from bacteria or mitochondria (19, 378, 380). Tentoxin also inhibits ATP synthesis in chloroplasts from the sensitive species. In contrast to the above, tentoxin at high concentrations strongly stimulates ATPase activity of CF1 (379) and partially reactivates the proton transport-coupled activity of the membrane-bound CF0F1 (369). Based on labeling studies, tentoxin-susceptible CF1 is considered to contain a high-affinity inhibitory binding site and one or two low-affinity stimulatory binding sites (69, 265, 317, 350). The binding of tentoxin to a low-affinity binding site releases the inhibitory effect caused by binding of tentoxin to the high-affinity binding site and reactivates the enzyme. The binding of a tentoxin molecule to the third site with very low affinity results in overactivation (265). In the crystal structure of the CF1-tentoxin complex, a tentoxin molecule is bound at the high-affinity binding site located in a cleft at an
β subunit interface. Here, it blocks the contact between Arg-297 and βAsp-83 (153, 155), restrains the movements of these residues, and also restrains conformational changes at the catalytic interface. This may arrest the catalytic β interface in the closed conformation and thereby hinder its transformation into the open conformation (153, 155). |
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TABLE 2. Tentoxin and tentoxin analogs
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Tyr3-TTX, MeTyr(Me)3-TTX, Phe3-TTX, dihydro-TTX, and Iso3-TTX are synthetic analogs of tentoxin in which an amino acid residue is mutated at the residue number indicated (316, 351) (Fig. 2C). MeSer1-TTX appears to inhibit isolated CF1 and the membrane-bound enzyme (CF0CF1) in thylakoids and proteoliposomes the same way and with the same efficiency as tentoxin. However, MeSer1-TTX exhibits much weaker reactivation of CF1 than tentoxin at high concentrations (69). On the other hand, MeTyr(Me)3-TTX shows similar activities as tentoxin in both inhibitory and stimulatory potencies (69). MeSer(Bn)1-TTX, MeGlu1-TTX, Glu(tBu)1-TTX, Lys2-TTX, and MeSer1-TTX analogs exhibit inhibitory activities with lower affinities but show no stimulatory effects (69). The leucinostatins (A to D, H, and K) are nonapeptide antibiotics produced by Paecilomyces (Fig. 2D and Table 3). Leucinostatin A is produced by Paecilomyces lilacinus, P. marquandii, and P. abruptus (434), leucinostatin B by P. lilacinus, and P. marquandii (266), leucinostatin C by P. lilacinus (259), leucinostatin D by P. lilacinus and P. marquandii (259, 339), and leucinostatin H and K by P. marquandii (259, 339). Leucinostatins adopt an
-helical conformation, and contains three Aib residues and some uncommon amino acid residues (71). Different types of leucinostatin differ in the kinds of amino acid at position 2 (Dec or Leu) and in the substitution pattern at the terminal nitrogen atom [-N(CH3)2, -NHCH3, -NH2, or -NO(CH3)2]. Leucinostatins bind to the F0 part of ATP synthases (127, 404, 439) and inhibit oxidative phosphorylation in mitochondria and photophosphorylation in chloroplasts (224, 242, 328). Leucinostatins have no inhibitory activity on isolated F1-ATPase (127, 439). |
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TABLE 3. Leucinostatins and efrapeptins
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E, TP, and the -helical structure of the subunit. The binding of efrapeptin is stabilized predominantly by hydrophobic interactions between efrapeptin and the residues in the cavity and also by two potential intermolecular hydrogen bonds (2). Efrapeptin is believed to inhibit the ATP synthase by preventing the βE subunit from converting into a nucleotide binding conformation. |
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Phytochemicals are naturally occurring bioactive nonnutrient compounds derived from plants. They possess chemopreventive or chemotherapeutic effects associated with reduced risk of various diseases, including cancer, and they bind to multiple molecular targets in the body (30, 286, 395). Phytochemicals are categorized into various groups, and among these are the polyphenolic phytochemicals. Some of the polyphenolic phytochemicals, many of which are phytoestrogens, bind to the ATP synthase and inhibit its ATPase activity. (Fig. 3) (143, 448, 449). The effects of polyphenolic phytochemicals on the ATPase activity of ATP synthase are additive, and the phenolic structures that comprise the polyphenolic phytochemicals play an important role in their inhibitory potencies (448). Two or more phenolic structures appear to be required, and the position of hydroxy groups seems to affect significantly the inhibitory effectiveness of polyphenolic phytochemicals on the ATP synthase (448).
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FIG. 3. Structures of polyphenolic phytochemicals, estrogens, and structurally related compounds. (A) Stilbenes. SITS, 4-Acetamido-4'-isothiocyanostilbene 2,2'-disulfonate; DIDS, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid. (B) Flavones and isoflavones. (C) Other polyphenolic phytochemicals. ECG, epicatechin gallate; EGCG, epigallocatechin gallate. (D) Steroidal estradiols and estrogen metabolites.
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Stilbenes consist of two phenolic rings linked by a spacer containing a double bond (Fig. 3A). Stilbene phytoalexins, resveratrol, and piceatannol are natural phytochemicals found in grapevine organs such as berries, leaves, canes, and roots. They inhibit the ATPase activity of mitochondrial ATP synthase by targeting the F1 catalytic headpiece (Table 4) (325, 448, 449). The mode of inhibition by resveratrol is mixed (448). In contrast to the above, resveratrol and piceatannol show no inhibition of ATPase activity of F1 from thermophilic Bacillus strain PS3 (TF1) (143). Resveratrol and piceatannol bind to a hydrophobic pocket between the hydrophobic tip in the C-terminal region of the
subunit and the hydrophobic inside of an annulus provided by the βTP subunit (142). The binding of these inhibitors, stabilized by hydrophobic interactions and hydrogen bonds, is believed to block the rotation of the subunit, inhibiting both the hydrolysis and synthesis of ATP. Resveratrol and piceatannol are bound to a single binding site in F1, and there are no equivalent sites between the subunit and either the βDP or βE subunit. |
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TABLE 4. Stilbenes
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20% inhibition at 60 µM. The binding site of DES is considered to be structurally distinct from other types of F0 inhibitors, as DES provides no protection against the inhibition of the F0F1 complex by N,N'-dicyclohexylcarbodiimide (DCCD), which is protected by oligomycin, venturicidin, and tricyclohexyltin. The combination of DES and DCCD produces a synergic inhibitory effect at low concentrations (<20 µM). 4-Acetamido-4'-isothiocyanostilbene 2,2'-disulfonate and 4,4'-di-isothiocyanatostilbene-2,2'-disulfonic acid are structurally very analogous and have been known as anion exchanger inhibitors. They also bind to ATP synthase and inhibit its catalytic activity. 4-Acetamido-4'-isothiocyanostilbene 2,2'-disulfonate strongly inhibits the ATPase activity of both F1 and F0F1 from Vibrio parahaemolyticus (290, 344). 4,4'-Di-isothiocyanatostilbene-2,2'-disulfonic acid also inhibits both the hydrolysis and synthesis of ATP in submitochondrial particles (SMP) and also ATP hydrolysis of isolated F1 from rat liver mitochondria (40).
Flavones and isoflavones are flavonoid-related polyphenolic compounds. Flavones and isoflavones differ in the position of a phenyl group on the 4H-1-benzopyr-4-one skeleton. Flavones are produced in various plants, whereas isoflavones are produced almost exclusively by beans. The flavones, quercetin, kaempferol, morin, and apigenin inhibit ATP hydrolysis (Fig. 3B). Specifically, quercetin inhibits the ATPase activities of mitochondrial F1 (MF1) and F0F1 (223, 448, 449) and also these activities in spinach chloroplasts (96), Escherichia coli (130), and Clostridium thermoaceticum (190). However, quercetin inhibits neither the ATPase activity of TF1 (343), a thermophilic bacterial ATP synthase, nor the ATP synthetic activity of mitochondrial ATP synthase (F0F1) (223). In contrast, quercetin has a stimulatory effect on photophosphorylation (218). Kaempferol and morin have inhibitory potencies similar to that of quercetin on the ATPase activity of mitochondrial F0F1, while apigenin, in which the 3-hydroxyl group in the chromone moiety is absent, shows about half the inhibitory potency (Table 5) (448).
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TABLE 5. Flavones and isoflavones
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Catechins are flavonoid compounds called flavan 3-ols. They are abundant in green tea, which includes four main catechins, epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin gallate. Among the catechins, epicatechin gallate and epigallocatechin gallate are inhibitors of the ATP hydrolysis activity of ATP synthase (Fig. 3C) (448). Epigallocatechin gallate, in which one more hydroxyl group is attached in the catechol moiety of epicatechin gallate, shows about three times higher potency than epicatechin gallate in the inhibition of ATPase activity of mitochondrial F0F1.
Grape seed proanthocyanidin extract, curcumin, an active ingredient of the Indian curry spice, and phloretin from apples inhibit the ATPase activity of mitochondrial F0F1. Theaflavin, a phytochemical from tea, and tannic acid, anionic polymers from the bark of trees, also exhibit inhibitory effects on the ATPase activity of mitochondrial F0F1 (Table 6) (448).
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TABLE 6. Other polyphenolic phytochemicals
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Endogenous steroidal estradiols and estrogen metabolites have inhibitory effects on mitochondrial ATP synthase (Fig. 3D and Table 7) (451). Two catecholestrogens, 4-hydroxyestradiol and 2-hydroxyestradiol, inhibit the ATPase activity of the mitochondrial ATP synthase, and the 4-hydroxyestradiol is about twofold more effective than the 2-hydroxyestradiol. 17β-Estradiol and 17
-estradiol inhibit the ATPase activity of solubilized brain mitochondrial fractions by 7 and 25% at 14 and 42 µM, respectively. Two micoestrogens, -zearalenol and β-zearalenol, also inhibit mitochondrial F0F1-ATPase activity. The I50 value of -zearalenol is about 50 µM, and the inhibitory potency of -zearalenol is about three- to fourfold stronger than that of β-zearalenol. The mechanism of inhibition by the steroidal estradiols and estrogen metabolites is not defined clearly, but the ATP synthase OSCP subunit has been identified as an estradiol binding protein, and it has been suggested that the inhibition is mediated by the binding of estrogens to OSCP (450). |
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TABLE 7. Steroidal estradiols and estrogen metabolites
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Polyketides are polymers of two-carbon ketide units synthesized by polyketide synthases. Macrolides belong to the polyketide class and contain a macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached (Fig. 4). Some natural macrolides, apoptolidin, cytovaricin, oligomycin, ossamycin, and venturicidin are elaborated by Nocardiopsis spp. and various strains of Streptomyces and are known as potent inhibitors of ATP synthase (Table 8) (205, 207, 225, 330, 358, 359). The binding sites of the macrolide inhibitors are located within the F0 part of the complex.
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FIG. 4. Structures of polyketide inhibitors.
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TABLE 8. Polyketide inhibitors
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Peliomycin, produced from various strains of Streptomyces (323, 358), is cytotoxic to mammalian cells, with limited antimicrobial and antifungal activities. The inhibitory properties of peliomycin on ATP synthesis by oxidative phosphorylation in mitochondria mimic those of rutamycin (423).
Venturicidin consists of three different types, A, B, and X, where venturicidin X is an aglycone of venturicidin A or B (401). It binds to subunit c of the ATP synthase and inhibits both proton translocation and membrane-bound ATPase activities from bacteria, chloroplasts, and mitochondria (62, 251, 311, 423, 447). The region conferring venturicidin resistance or hypersensitivity in ATP synthase is located in the middle of the membrane, and most of this region overlaps with that for oligomycin resistance (123, 131, 280).
Ossamycin is a 24-membered macrolide produced in Streptomyces hygroscopicus subsp. ossamyceticus (209, 359). Ossamycin inhibits both the ATPase and oxidative phosphorylation activities of mitochondrial ATP synthase (150, 423). It has no direct effect on E. coli F1 (EF1) or F0, but it does inhibit ATP-driven proton transport by uncoupling ATP hydrolysis from proton transport (311). The binding site of ossamycin in mitochondrial ATP synthase lies close to the boundaries of regions that cause oligomycin and venturicidin resistance in subunit c. This site contains residues Leu53 to Leu57 (yeast sequence) in the C-terminal transmembrane helix (131).
Apoptolidin and cytovaricin are 20- and 26-membered macrolides found in Nocardiopsis spp. and Streptomyces sp. strain H-230, respectively. Both apoptolidin and cytovaricin inhibit membrane-bound mitochondrial ATP synthase. The precise binding sites of apoptolidin and cytovaricin are not yet defined. However, they are believed to be located at regions where oligomycin and ossamycin bind, as the chemical backbones of these inhibitors are structurally similar to those of oligomycin and ossamycin (349).
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Organotin compounds are organic compounds that contain tin. They are classified as R4Sn, R3SnX, R2SnX2, and RSnX3. Among these, R3SnX organotin compounds have been used as biocides and pesticides and are known to inhibit ATP synthase (Fig. 5) (148-150, 190, 252, 403-405, 418, 437). Some R4Sn organotin compounds, such as tributyltin 3-hydroxyflavone, also inhibit ATP synthase (405). The organotin compounds inhibit both ATP hydrolysis and ATP synthesis catalyzed by the membrane-bound and isolated F0F1 complex. However, they have no effect on the ATPase activity of isolated F1 (Table 9). Organotin compounds react noncovalently with the ATP synthase, and the inhibitory effect of the compounds is reversed by mono- and dithiols such as dithiothreitol and mercaptoethanol (437). The sites of action of organotin compounds are located in the ion channel within subunit a. Here, they are believed to inhibit ATP synthase by competing with Na+ or H+ for the same binding site (418). Diorganotin-3-hydroxyflavone complexes such as dibutyltin 3-hydroxyflavone bromide and diphenyltin 3-hydroxyflavone chloride show a marked fluorescence enhancement on binding to mitochondrial ATP synthase (405).
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FIG. 5. Structures of organotin compounds and structural relatives.
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TABLE 9. Organotin compounds and structural relatives
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-PYRONE DERIVATIVES
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-Pyrone (or 2-pyrone) is a six-membered cyclic unsaturated ester. Its derivatives are widely distributed in nature, and some -pyrone-containing mycotoxins, such as aurovertin, citreoviridin, and asteltoxin, inhibit ATP synthase by targeting F1 (Fig. 6).
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FIG. 6. Structures of polyenic -pyrone derivatives.
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-Glu399 of TP. However, in βE the pyrone ring has no equivalent interaction with E, as the aurovertin bound in βE is too far from E. The interactions between aurovertin and amino acids are mainly hydrophobic. In βDP, the interface between DP and βDP is tightly packed, making the aurovertin binding pocket inaccessible (410). In the binding of aurovertin to F1, β-Arg398 (E. coli sequence) appears to play an important role, as mutations in this residue confer aurovertin resistance (230, 231, 424). In bacteria that are naturally resistant to aurovertin, the β-Arg398 residue is replaced with other amino acid residues (172, 343). Aurovertin is believed to inhibit F1 by preventing catalytic interface closure involved in the cyclic interconversion of catalytic sites (410, 430). In addition, aurovertin increases the affinity of F1 for phosphate (307). Aurovertin fluoresces weakly at 470 nm, and this is enhanced by 50- to 60-fold when aurovertin binds to F1 (74, 136, 232). The fluorescence increase is considered to be due to the limited mobility of aurovertin at its binding site and has been used to monitor inhibition of F1-ATPase activity (74, 136). |
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TABLE 10. Polyenic -pyrone derivatives
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Citreoviridin, produced by some molds of the genera Penicillium and Aspergillus, inhibits the ATPase activities of F1 from bacteria and mitochondria by binding to the ATP synthase β subunit (136, 353) (Table 10). However, ATP synthases from some species are resistant (404, 439). In sensitive species, citreoviridin acts as an uncompetitive inhibitor of ATP hydrolysis by soluble and membrane-bound ATP synthase and as a noncompetitive inhibitor of ATP synthesis by the membrane-bound ATP synthase enzyme (354). The binding of citreoviridin to F1 or its isolated β subunit is noncompetitive with respect to aurovertin (136). Although the binding site of citreoviridin within the β subunit is not clarified, it has been suggested that citreoviridin and aurovertin interact at separate sites (136). Citreoviridin fluoresces weakly at 530 nm when irradiated at 380 nm. However, unlike aurovertin, enhancement is not observed when bound to F1 (233). Light converts citreoviridin to its stereoisomer, isocitreoviridin, which has no effect on either ATP hydrolysis or ATP synthesis catalyzed by ATP synthase (354).
Asteltoxin is made in Aspergillus stellatus Curzi and Emericella variecolor. It contains a unique 2,8-dioxabicyclooctane ring and inhibits both BF1 and MF1 with a stoichiometry of 1:1 in the presence of ADP (Table 10) (200, 352). As asteltoxin fails to inhibit aurovertin-resistant mutants, it is believed to bind to the same site as aurovertin (352). Asteltoxin binding to F1 shows an enhancement of fluorescence (emission maximum, 470 nm; excitation maximum, 385 nm). The ADP-stimulatory effect and the Mg2+-quenching effect on the fluorescence enhancement of asteltoxin binding are similar to those observed for aurovertin. However, the stimulatory effect on phosphate binding to F1 observed with aurovertin is not observed with asteltoxin (352).
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Amphiphilic cationic dyes containing a basic amine group and a lipophilic portion (Fig. 7A) inhibit the ATPase activities of both F1 and F0F1. Most exhibit a stronger inhibitory effect on the ATPase activity of F0F1 than on that of F1 (Table 11).
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FIG. 7. Structures of cationic inhibitors. (A) Amphiphilic cationic dyes. EtBr, ethidium bromide. (B) TALAs and related compounds. (C) Other organic cations. DPBP, 4,4-diphenyl-2,2-bipyridine; PDT, 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine.
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TABLE 11. Amphiphilic cationic dyes
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Rosaniline, malachite green, and brilliant green are closely related in structure. Rosaniline and malachite green inhibit MF1 in a parabolic mixed fashion, indicating at least two binding sites at high concentrations (52).
Quinacrine inhibits reversibly the ATPase activities of EF1 and bovine MF1 with a similar inhibitory potency (220, 268). This agent inhibits the ATP hydrolysis activity of F1 competitively when Mg2+ is at a constant concentration and ATP at a variable concentrations (220, 268). Quinacrine mustard is a quinacrine derivative in which a diethyl group attached to the tertiary amino group is replaced by a bischloroethyl groups. The quinacrine mustard binds to F1 and alkylates β subunits. The inhibition of the ATPase activity of F1 by quinacrine mustard is irreversible (220) and is due, at least in part, to modification of one or more of the carboxylic acid side chains in the β subunit DELSEED region and possibly also to modification of unspecified amino acid side chains between residues β302 and 356 in the bovine sequence (53). The rate of inactivation of MF1 and TF1 by quinacrine mustard is inhibited by ATP, whereas the rate of inactivation of EF1 is stimulated by ATP (54).
Acridine orange and coriphosphine are acridine derivatives that inhibit the ATPase activity of MF1 in a mixed fashion (52). Pyronin Y, a xanthene derivative, inhibits the ATPase activities of F0F1 from mitochondria and E. coli (52, 268). Here, the inhibitory effect on the mitochondrial ATPase is more potent for F0F1 (>100-fold) than for F1 (52).
Dequalinium is a quinoline derivative that inhibits the ATPase activities of F1 from both mitochondria and bacteria (52, 268, 296, 329, 452). Dequalinium inhibits chloroplast Ca2+-ATPase, whereas it stimulates chloroplast Mg2+-ATPase (329). The inhibition of ATPase activity by dequalinium is reversible, hyperbolic, and noncompetitive for MF1 and TF1 in the dark (52, 268, 296, 329, 452). A long lag is observed in the inhibition of TF1 by dequalinium that is not observed for the inhibition of MF1 (296). Dequalinium, upon illumination at 350 nm, inactivates F1-ATPase with pseudo-first-order kinetics (296, 329, 452, 454). This is accompanied by derivatization of βPhe420 in TF1 (296), βMet183 in CF1 (329), and Phe403, Phe406, and a side chain within residues 440 to 459 of the β subunit in bovine heart MF1 (454).
Safranin O inhibits the ATPase activities of membrane-bound F0F1 from both bovine heart mitochondria and E. coli (52, 268). Safranin O also inhibits soluble MF1 with weaker inhibitory potency (52). Nile blue A inhibits the ATPase activity of membrane-bound F0F1 from mitochondria, whereas it has no inhibitory effect on isolated F1 (52). Ethidium bromide inhibits noncompetitively ATP hydrolysis by both MF1 and F0F1 from Saccharomyces cerevisiae (82, 433), with similar inhibitory potencies (66, 82).
Tertiary amine local anesthetics (TALAs) are composed of an aromatic portion, an intermediate chain, and a terminal amine group (Fig. 7B) (370). The intermediate chain contains either an ester (tetracaine and procaine) or an amide (dibucaine and lidocaine) group. In procainamide, the ester group in procaine is replaced with an amide. Chlorpromazine and trifluoroperazine are cationic phenothiazine derivatives. The TALAs are known to inhibit primarily sodium influx through sodium-specific ion channels in the neuronal cell membrane. However, they can also bind to ATP synthases from mitochondria and some bacteria and can inhibit ATP hydrolysis activity (Table 12) (76, 406).
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TABLE 12. Tertiary amine local anesthetics and related compounds
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In contrast to the case for the mitochondrial ATP synthase, the TALAs inhibit bacterial ATP synthases selectively. For example, they exhibit no inhibition of F1 from the thermophilic bacterium PS3 under the conditions tested (343). However, tetracaine and dibucaine do inhibit the ATPase activity of the membrane-bound ATP synthase from the bacterium Mycobacterium phlei (4), whereas procaine and lidocaine show no inhibitory effects. In addition, tetracaine and dibucaine show no or partial inhibition of the ATPase activity of soluble F1, in contrast to full inhibition of the ATPase activity of the membrane-bound ATP synthase. Upon inhibition (uncompetitive) of the membrane-bound ATP synthase from M. phlei by tetracaine and dibucaine, proton conductivity is markedly inhibited. Tetracaine and DCCD are not mutually exclusive in binding to the ATP synthase from M. phlei, and they appear to bind to separate binding sites within the proton-translocating "F0" region (4).
Chlorpromazine and trifluoroperazine interact with various subunit types of F1 and F0. Both bind to membrane-bound subunits more readily than to soluble subunits, with trifluoroperazine binding to hydrophobic subunits more extensively than chlorpromazine (88). The binding sites of chlorpromazine and trifluoroperazine are not identical and mutually nonexclusive (87, 88). Upon photoactivation with UV light, the phenothiazine moiety of chlorpromazine and trifluoroperazine forms covalent bonds with the ATP synthase, leading to its irreversible inhibition. In other studies, chlorpromazine has been shown to protect MF1 and EF1 against both cold-induced dissociation and inactivation by DCCD (54). This agent is believed to cause inhibition by interacting with the catalytic site at position βGlu188 (bovine sequence). However, in other studies, chlorpromazine has been shown to stimulate the ATPase activity of TF1 both at 37°C and at low concentrations (below 0.6 mM) at 23°C. It shows no inhibition up to 1.2 mM at 37°C or 60°C (54).
Propranolol is a nonselective beta blocker for the treatment of hypertension. It is not a TALA and has no ester or amide group in the intermediate chain. However, it is structurally analogous to TALAs. The main action of propanolol is to block the action of epinephrine on both β1- and β2-adrenergic receptors, but it also targets ATP synthase. Propranolol inhibits the mitochondrial ATPase activities of both membrane-bound ATP synthase and isolated F1 (76, 343). It also inhibits TF1 at both 37°C and 60°C with nearly the same effective concentrations as that for inhibition of membrane-bound mitochondrial ATP synthase (76, 343).
Alkylguanidines (Fig. 7C) that possess an alkyl chain of more than six carbons inhibit the ATPase activities of both membrane-bound and isolated MF1 (92, 300). The inhibition by octylguanidine, an alkylguanidine, is fully reversible, and the octylguanidine prevents cold-induced dissociation of F1 (92).
1-Dansylamido-3-dimethypropylamine compounds are dansylated organic cationic inhibitors (Fig. 7C). They inhibit both ATP hydrolysis and ATP synthesis at similar concentrations (116). The 1-dansylamido-3-dimethypropylamine compounds inhibit the ATPase activities of both isolated and membrane-bound F1 and exhibit more potent inhibitory effect on the membrane-bound F1 than the isolated enzyme. The 1-dansylamido-3-dimethypropylamine compounds with longer alkyl groups (decyl and hexadecyl) have stronger inhibitory activity than those with short groups (propyl and hexyl) (Table 13). The binding site(s) of these compounds is not clarified but is considered to be located on the β subunit (116).
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TABLE 13. Other organic cations
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Spermine and spermidine are polyamines distributed widely in nature. Both activate the ATPase activity of membrane-bound ATP synthase at low physiological concentrations (312, 374) and inhibit it at high concentrations (185). Spermine and spermidine also inhibit the ATPase activity of isolated F1. Inhibition by spermine (1 to 2 mM range) is much greater than that by spermidine (2.5 to 5 mM range) and is uncompetitive with variable concentrations of ATP in the presence of Mg2+ but competitive when both ATP and Mg2+ concentrations are variable. Spermine and spermidine bind to ATP, an event that is inhibited by Mg2+. In fact, the inhibition of the ATPase activities of membrane-bound and isolated F1 by polyamines is considered to be due to their direct binding to ATP. In contrast to their ATPase-inhibitory actions, spermine and spermidine stimulate catalysis in SMP of both succinate-dependent ATP synthesis and Pi-ATP exchange (185).
Octahedral bathophenanthroline (BPh3)-metal chelates inhibit MF1 in an uncoupler-reversible fashion (63-65, 315). They bind to the ATP synthase β subunit and form a complex with a stoichiometic ratio of 3 mol BPh3-Me2+/mol F1. Full inhibition is observed with 0.67 µM of BPh3-Fe2+ for MF1 from bovine heart (63). BPh3-Fe2+ competes with aurovertin for binding to the β subunit. The inhibition is relieved by addition of uncouplers of oxidative phosphorylation via a process that involves direct interaction of the uncouplers with the inhibitory chelates. In fact, inhibitor-uncoupler adducts are believed to be formed (63). BPh3-Ni2+ and BPh3-Ru2+ are equally efficient inhibitors in the uncoupler-reversible inhibition of MF1 (63, 65). Moreover, BPh3-Fe2+ protects F1 from cold-induced dissociation and light-induced inactivation by Rose bengal in an uncoupler-reversible manner (64). The related chelates 4,4-diphenyl-2,2-bipyridine and 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine with Fe2+ also inhibit MF1, but with weaker inhibitory potencies than BPh3-metal chelates (63).
Atrazine is a globally used triazine herbicide that inhibits photosynthetic electron transport by binding the plastoquinone binding protein in photosystem II (382). Atrazine also targets ATP synthase from sperm and mitochondria, inhibiting the ATP synthesis activity of ATP synthase (170). The amino derivative of atrazine in which a terminal methyl group is replaced with an amino group is more potent in inhibition of ATP synthesis.
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Arsenate mimics the
-phosphate of ATP. It inhibits ATP synthesis at the active site of ATP synthase by competing with phosphate (Fig. 8 and Table 14) (81, 264, 307). Arsenate blocks the Pi
H2O exchange and also the ATP Pi exchange catalyzed by the ATP synthase (201) and is a more effective inhibitor when the concentration of phosphate is low (307). Thus, at 40 µM phosphate, 4.6 mM arsenate inhibits phosphate binding to bovine heart MF1 by 84%.
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FIG. 8. Structures of phosphate analogs.
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TABLE 14. Phosphate analogs
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-phosphate of ATP (48, 107, 195, 243, 256). The inhibition by these fluorides of aluminum and beryllium involves ADP, Mg2+, and the fluoride ion (F–). In fact, no inhibition occurs without fluoride. Inhibition also occurs when IDP, GDP, or CDP replaces ADP (187, 243). Aluminum fluoride and beryllium fluoride inhibit F1 to the same extent via a "quasi-irreversible" process (243). The inhibitory species recognized by F1 are AlF3 and AlF4– for aluminum fluoride (48, 256) and BeF+, BeF2, and BeF3– for beryllium fluoride (187, 195). In crystals of F1 grown with ADP and one of the inhibitors (AlF4– or BeF3–), two catalytic sites are occupied, one in the βTP subunit and the other in the βDP subunit (195, 256). Only one catalytic site, βDP, is occupied with aluminum fluoride (AlF3) in the crystal grown in the presence of ADP, adenylyl imidodiphosphate (AMP-PNP), and the inhibitor. No bound aluminum fluoride or beryllium fluoride is found in the and βE subunits. Three basic residues located in the vicinity of the -phosphate site, βLys162, βArg189, and Arg373, are involved in coordination of the inhibitors and are considered to provide charge stabilization (256). Scandium fluoride (ScFx) binds to F1 of ATP synthase and inhibits its ATPase activity (279). ScFx forms a tight-binding inhibitory ternary complex with MgADP at the catalytic sites, and the MgADP·ScFx complex acts as a transition state analog. The inhibition by ScFx is Mg2+ dependent, and ADP is also required for strong inhibition. The inhibition is reversible, and the ATPase activity is slowly regained in a single exponential reactivation process.
Two vanadate species, VO43– and VO3–, inhibit F1-ATPase (77, 210, 211, 344). Orthovanadate (VO43–) binds to the catalytic sites and forms a transition-like state MgADP·Vi-F1 complex in the presence of ADP and Mg2+. The inhibition of rat liver MF1 by orthovanadate is reversible, with a restoration of original activity to a level close to 90% (210, 211), whereas EF1 is resistant to orthovanadate (6). In the presence of UV and O2, the cleavage of the β subunit from rat liver MF1 occurs at position Ala158 in the P-loop (210, 211). In the crystal structure of F1 with vanadate from the same source, one vanadate ion is found in each catalytic site of the β subunit (77). The vanadate in this transition-like state is located in a charged pocket surrounded by βLys162, βGlu188, βArg189, and βArg260 and is complexed with ADP and Mg2+. Moreover, the vanadate is positioned closer to P-loop βAla158 than is phosphate in the F1-ADP,Pi ground state structure. It has been proposed that the positioning of βAla158 closer to the -phosphate of ATP in the transition state may help facilitate the dehydration of ADP and Pi (to give water) and therefore facilitate ATP synthesis (77).
Magnesium fluoride inhibits F1 by acting also as an apparent transition state analog in combination with MgADP (5). Like vanadate, it mimics the -phosphate of ATP in the transition state. The inhibition is slow and reversible and requires ADP.
Sulfite is known as an effective activator of F1-ATPase. However, it can also play a role as an inhibitor of the reversal of ATP synthase as a mixed-type inhibitor in the presence of ADP and phosphate (Fig. 8 and Table 14). The sulfite diminishes the rate of ATP synthesis of Paracoccus denitrificans with an I50 of 3.5 mM (295). The mechanism of sulfite inhibition is uncertain, but it has been suggested that the action of inhibitory ADP is involved in the binding of nucleotides to noncatalytic sites (249), and the binding of sulfite to the noncatalytic sites increases the Ki for inhibitory ADP (295, 327).
Thiophosphate is a group of compounds in which a phosphorus atom is bonded to one or more sulfur and zero or more oxygen atoms, and it is found in a number of insecticides. A thiophosphate, SPO33–, has been shown to inhibit ATP synthesis in mitochondria (254, 363). It inhibits the Pi ATP exchange in SMP from bovine heart mitochondria competitively and also inhibits ATP synthesis noncompetitively with respect to ADP without a change in Km for ADP (363). In contrast, in pea SMP, thiophosphate decreases the Km of the enzyme for ADP (254).
Azide inhibits the ATPase activity of F1 from mitochondria, bacteria, and chloroplasts (25, 46, 126, 274, 278, 287, 391, 412). Azide has no inhibitory effect on ATP synthesis (25). The inhibition by azide is noncompetitive (287, 391) and occurs only in the presence of ADP and ATP (274). The binding of inhibitory azide requires prior binding of both ADP and Mg2+ (160, 278). Azide binds to the catalytic site in βDP of F1 and resides adjacent to the β-phosphate of ADP, mimicking the nonbridging oxygen atom of the -phosphate (46). The binding of azide in the βDP catalytic site is very tight, and the azide is closely associated via hydrogen bonds with βLys162 in the P-loop and Arg373 (46). The inhibition is dependent on ATP concentration (274) and is reversed by addition of phosphate, possibly by competing for the azide binding site (262, 274).
Azido-2-nitrophenyl phosphate (ANPP) is a photoaffinity phosphate analog in which the 4-azido-2-nitrophenyl group is attached to phosphate (Fig. 8 and Table 14). ANPP inhibits F1 as a competitive inhibitor in the dark by specifically targeting -phosphate binding sites within the nucleotide binding pockets on the β subunit of isolated F1 or on both and β subunits of membrane-bound F0F1 (154, 227). However, upon photoirradiation with visible light, ANPP inactivates the enzyme by binding covalently to these subunits. This occurs most frequently on βTyr 311, together with βIle304 and βGln308 in MF1, and on the analogous βTyr 328, together with βVal329 and βPro330 in CF1 (133, 258). Phosphate added before photoirradiation protects the photoinactivation by ANPP. The stoichiometry for full photoinactivation of F1 is approximately 1 mol of ANPP/mol of CF1 (321).
Divalent metal ions are usually activators of F1, but in their free form, they can also function as inhibitors at high concentrations (47, 98, 174, 278, 291, 365). Free Mg2+ acts as a linear competitive inhibitor (98, 365). The inhibition of CF1 by free Mg2+ requires the presence of a tightly bound ADP at the catalytic site (160, 278). The Ki values are variable, and CF1 and BF1 are about 2 orders of magnitude more sensitive to the inhibition by free Mg2+ than is MF1. Free Mn2+ and Ca2+ ions also inhibit F1-ATPase in a competitive manner and are more effective than free Mg2+ in inhibition of CF1 (Table 15) (174).
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TABLE 15. Divalent metal ions
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Excess free ATP is also an inhibitor of ATP synthase (Tables 16 and 17 and Fig. 9A) (98, 291, 365). Inhibition of ATPase activity of F1 by free ATP can be competitive (in the photosynthetic bacterium Rhodospirillum rubrum [291], biphasic (in Phycomyces blakesleeanus [98], or second order/parabolic (in ox heart mitochondria (365).
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TABLE 16. Properties of purine nucleotides and nucleotide analogs
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TABLE 17. Inhibitory potencies of purine nucleotides and nucleotide analogs
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FIG. 9. Structures of purine nucleotides and nucleotide analogs. (A) Nucleotides and nucleotide analogs. (B) Azidonucleotides.
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GTP and formycin 5'-triphosphate (FTP) bind to empty noncatalytic sites on CF1 in the presence of Mg2+ and inhibit its ATPase activity (159). Binding of GTP or FTP to two sites causes more inhibition than binding to one site, and the GTP has stronger inhibitory potency than FTP. With GTP or FTP bound at two noncatalytic sites, the GTP inhibits the ATPase activity about 90%, and the FTP about 80%. After a 15-min incubation period, about 50% maximal inhibition is achieved with 5 to 10 µM GTP or FTP for spinach CF1-ATPase.
2',3'-O-(2,4,6-trinitrophenyl) ATP (TNP-ATP) and TNP-ADP are ribose-modified chromophoric and fluorescent analogs of ATP and ADP in which a trinitrophenyl group is attached to the 2' and 3' hydroxyls of ribose (Fig. 9A). These compounds have been used widely for various assays of ATP binding to proteins. Both compounds are potent inhibitors of F1 with high affinity, and the TNP-ATP is hydrolyzable by F1 from mitochondria, chloroplasts, and bacteria (157, 219, 273, 368, 429). The inhibition of ATP hydrolysis by TNP-ATP or TNP-ADP has been reported to be competitive (157) or biphasic (277). These nucleotide analogs bind to both catalytic and noncatalytic sites of F1. Their binding is noncooperative at the three noncatalytic sites and cooperative at the three catalytic sites (429).
2-Azido-TNP-ATP, a 2-azido derivative of TNP-ATP, inhibits F1 catalyzed ATP hydrolysis biphasically (Fig. 9B and Table 18) (276). Bicarbonate decreases the degree of inhibition by 2-azido-TNP-ATP. The Km and Vmax for 2-azido-TNP-ATP hydrolysis are similar to those for TNP-ATP hydrolysis. Upon UV illumination of the F1-ATPase complex with the bound 2-azido-TNP-ATP, it is incorporated into the complex covalently and inactivates the F1-ATPase irreversibly.
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TABLE 18. Azidonucleotides
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subunits and one β subunit of MF1 from bovine heart are low (Kd = 1 to 2 µM), whereas the affinities for the other two β subunits are very high (Kd <10 nM) (428). Inhibition by lin-benzo-ADP is competitive and has complex kinetics of inhibition. Lin-benzo-ADP is fluorescent, and its fluorescence spectrum is extensively quenched by adding F1. As expected, this fluorescence quenching is reversed by adding ADP (199). 5',5'-Diadenosine oligophosphates (APxA) are compounds which have a chain of phosphoryl groups linking two adenosine moieties. The APxA that have a long chain of phosphoryl groups (AP4A, AP5A, and AP6A) has been shown to inhibit the ATP hydrolysis activity of MF1, whereas compounds that have a shorter chain (AP2A and AP3A) showed stimulatory effects (417). The inhibition by AP4A, AP5A, and AP6A required the presence of at least one vacant noncatalytic site, and the maximal level of inhibition was 80%. AP4A was the most potent, and its stoichiometry for maximal inhibition was near 1 mol/mol of F1. In contrast, a contradictory result has also been reported in the inhibition of the same enzyme by AP5A, and no inhibition was observed up to 100 µM (325).
AMP-PNP is a nonhydrolyzable ATP analog in which the terminal bridge oxygen of the triphosphate moiety is replaced by an NH group (444). AMP-PNP has been used widely in kinetic studies of F1 and has been found to be a potent competitive inhibitor in ATPase assays of either the soluble or membrane-bound enzyme from bovine heart (37, 147, 306, 361) However, AMP-PNP is reported to be noncompetitive in ATPase assays with membrane-bound rat liver F1 (361). The Ki values reported are variable (14 nM to 0.5 µM) (37, 84, 255, 306, 361). AMP-PNP has no effect on the ATP synthesis activity of ATP synthase, although it is a potent inhibitor of F1-catalyzed ATP hydrolysis (302, 306). It binds to both catalytic and noncatalytic sites, and when it is bound to the latter sites, it induces hysteretic inhibition to the same extent as ADP (34, 37).
Guanylyl imidodiphosphate (GMP-PNP) and inosine-5'-[(β,)-imido]triphosphate (IMP-PNP) are analogs of GTP and ITP, respectively, in which the bridge oxygen atom between the β and phosphorus atoms is replaced by an NH group. The inhibition by GMP-PNP versus GTP and ITP is competitive (361), whereas inhibition versus ATP is competitive (37) or mixed (361). Unlike AMP-PNP, GMP-PNP shows no induction of hysteretic inhibition (34). IMP-PNP inhibits ITP hydrolysis potently, whereas it inhibits ATP hydrolysis only at low concentrations of ATP below 100 µM (362). At high concentrations of ATP, IMP-PNP stimulates the rate of ATP hydrolysis. In contrast, the stimulation of ATP hydrolysis by IMP-PNP is not seen in the presence of bicarbonate, and IMP-PNP inhibits ATP hydrolysis competitively.
Adenosine 5'-methylenediphosphate is an analog of ADP in which the bridge oxygen atom between the and β phosphorus atoms is replaced by a CH2 group. Adenosine 5'-methylenediphosphate inhibits ATP synthesis competitively with respect to ADP (254, 363) and inhibits Pi ATP exchange uncompetitively (363).
Exchange-inert metal-nucleotide complexes are stable, inert octahedral complexes of Cr(III), Co(III), or Rh(III) with ATP and ADP (383). The exchange-inert metal-nucleotide complexes inhibit ATP synthase by binding to F1 (44, 158, 383, 384, 432). Chromium complexes of ATP and ADP, i.e., ,β-CrADP, β,-CrATP, and ,β,-CrATP, are competitive inhibitors of MF1 with respect to MgATP (383, 432). β,-CrATP and ,β,-CrATP inhibit F1 by binding at the catalytic site and ,β-CrATP by binding at a regulatory site (432). The binding sites show no significant selectivity for the steric arrangement of the chromium complexes. β,-CrATP and ,β,-CrATP bind to the catalytic site with the same affinity, although they have different steric arrangements of the chromium (β,-CrATP with monocyclic coordination at the metal ion and ,β,-CrATP with bicyclic coordination). Two diastereomers of ,β-CrADP (
and isomers) also exert similar inhibitory effects (432). Monodentate Cr(NH3)4ATP, bidentate/tridentate RhATP, bidentate Cr(NH3)4ATP, and bidentate Co(NH3)4ATP are mixed noncompetitive inhibitors of F1 (44, 158, 383, 384). All the amine and aqua exchange-inert metal-nucleotide complexes are mutually exclusive during ATP hydrolysis and appear to bind the same site(s) (383).
3'-acetyl ATP and 3'-acetyl ADP are monoacetylated adenine nucleotides in which an acetyl group is attached to the 3' hydroxyl group of ribose. 3'-Acetyl ATP and 3'-acetyl ADP inhibit the ATPase activity of MF1 in a competitive fashion with ATP and ADP, respectively (355, 394). They bind to catalytic sites, but no reactions occur; i.e., the 3'-acetyl ADP is not phosphorylated, and the 3'-acetyl ATP is not hydrolyzed (355).
3'-O-[1-(5-dimethylamino)-naphthoyl]ADP (F-ADP or DMAN-ADP) and 3'-O-(1-naphthoyl)ADP (N-ADP) are fluorescent analogs of ADP in which 5-dimethyl amino-naphthoyl and naphthoyl groups are attached to the 3' hydroxyls of ribose, respectively (356, 397, 427). Both inhibitors are potent competitive inhibitors of both ATP hydrolysis and ATP synthesis and exhibit a much stronger inhibition of ATP synthesis than of ATP hydrolysis (356, 397). F-ADP binds to three sites in bovine heart MF1 with Kd values of 50 nM for all sites, whereas the N-ADP binds to two sites with Kd values of 20 to 50 nM (397). F-ADP binds approximately 10 times more strongly than F-ATP (3'-O-[1-(5-dimethylamino)-naphthoyl]ATP), whereas F-AMP (3'-O-[1-(5-dimethylamino)-naphthoyl]AMP) is not inhibitory (356). ANA-ADP (3'-O-[5-azidonaphthoyl]-ADP) is a photoreactive analog of N-ADP (Fig. 9B and Table 18). It binds to the same site as N-ADP but with a lower affinity, i.e., about 2.5 times lower than the Ki of N-ADP for bovine heart MF1. Upon illumination, ANA-ADP rapidly photoinactivates F1 (240).
3'-O-(4-Benzoyl)benzoyladenosine 5'-triphosphate (BzATP) and BzADP are ribose-modified photoactivatable analogs of ATP and ADP in which a photoreactive (4-benzoyl)benzoyl group is attached to the 3' hydroxyls of ribose (Fig. 9A) (435). BzATP binds to the ATP synthase β subunits both isolated and complexed but binds only to isolated subunits (33). BzATP and BzADP bind to the catalytic site as competitive and reversible inhibitors in the absence of illumination. However, under actinic illumination, BzATP and BzADP inactivate F1 irreversibly by covalently modifying the catalytic site (3, 8, 435).
Other 3'-O-substituted adenine nucleotides include 3'-O-phenylacetyl-ADP, 3'-O-phenylbutyryl-ADP, 3'-O-benzoyl-ADP, 3'-O-[N-(2-nitrophenyl)--aminobutyryl]-ADP, 3'-O-[N-(4-nitrophenyl)--aminobutyryl]-ADP, 3'-O-naphthoyl-(1)-ADP, 3'-O-naphthoyl-(1)-ATP, 3'-O-naphthoyl-(2)-ADP, 3'-O-naphthyl-(1)-acetyl-ADP, 3'-O-naphthyl-(2)-acetyl-ADP, 3'-O-5-dimethylaminonaphthoyl-(1)-ADP, 3'-O-5-dimethylaminonaphthoyl-(1)-ATP, 3'-O-anthranoyl-(1)-ADP, and 3'-O-anthranoyl-(9)-ADP (356). These inhibitors inhibit oxidative phosphorylation in bovine heart SMP with Ki values in the range of 0.3 to 5.9 µM (Table 17).
The fluorosulfonylbenzoyl nucleotides 5'-p-fluorosulfonylbenzoylinosine (FSBI), 5'-p-fluorosulfonylbenzoyladenosine (FSBA), and 5'-p-fluorosulfonylbenzoylethenoadenosine (FSBA) bind to F1 and inactivate the enzyme by modifying amino acid side chains of and/or β subunits. FSBI binds to the β subunit reversibly and reacts covalently with a Tyr residue. The inactivation follows pseudo-first-order kinetics, and the residues modified are βTyr345 in bovine heart MF1 (49, 57) and βTyr364 in F1 from thermophilic bacterium PS3 (50). The modification of a Tyr residue in a single β subunit is sufficient to inactivate F1 completely (49).
FSBA binds reversibly to a single binding site on the β subunit of MF1 (101). This inactivates F1 irreversibly by forming a covalent bond via a process that follows pseudo-first-order kinetics (51, 101). The modified residues are Tyr244, Tyr300, and either βTyr368 or βHis427 (51, 56, 114, 407). The complete inactivation of F1-ATPase by FSBA requires the modification of all three copies of the β subunits, in contrast to that by FSBI (49). 8-azido-FSBA (5'-p-fluorosulfonylbenzoyl-8-azidoadenosine) binds to MF1 in the absence of light and inhibits ATPase activity. Upon illumination of the dark-inactivated F1, 8-azido-FSBA induces in high yield cross-linking between βHis427 and βTyr345 within the same β subunit (453).
FSBA binds to Tyr244 of MF1, inactivating ATPase activity with pseudo-first-order kinetics (152, 414). Maximal inactivation is achieved when FSBA modifies Tyr244 in one or two copies of the subunit. Inactivation of F1 by both FSBA and FSBA is stimulated by high concentrations of phosphate, whereas inactivation by FSBI is not greatly affected. Prior modification of F1 with FSBA completely prevents modification of Tyr244 by FSBA, while prior inactivation with FSBI allows considerable modification.
Adenosine oligophospho-pyridoxal compounds (APxPL) contain a chain of phosphoryl groups linking adenosine and pyridoxal moieties. Adenosine triphospho-pyridoxal (AP3-PL) binds to the catalytic sites of EF1 and inhibits hydrolytic activity by modifying and β subunits. The stoichiometric ratio of binding of AP3-PL for complete inactivation of F1 is about 1 mol of AP3-PL per 1 mol F1 (288). Addition of Mg2+ increases the inhibitory potencies of AP3-PL and also causes a change in the ratio of modification of and β subunits by AP3-PL from 4:1 in the absence of Mg2+ to 1:3 in its presence (184). The residues modified by AP3-PL are Lys201, βLys155, and βLys201 (184, 281, 390). Adenosine tetraphospho-pyridoxal (AP4-PL) binds to EF1 with the same concentration for half-maximal inactivation as AP3-PL and shows essentially the same absorption spectrum and binding kinetics (288). Adenosine diphospho-pyridoxal (AP2-PL or PLP-AMP) is a weak inhibitor compared to AP3-PL (288). It binds to Lys201 in the isolated subunit from E. coli with a maximal stoichiometry of approximately 1 mol/mol (Kd of 150 µM). It also impairs the reconstitution of subunits with β and subunits.
The 2',3'-dialdehydes of ATP, ADP, and AMP (oATP, oADP, and oAMP) are periodate-oxidized derivatives of ATP, ADP, and AMP in which the ribose ring is opened (Fig. 9A). In the presence of Mg2+, oATP is a substrate and acts as a competitive inhibitor of ATP hydrolysis. Prolonged incubation of the enzyme with oATP inactivates F1-ATPase activity irreversibly with pseudo-first-order kinetics by modifying both and β subunits (95, 219, 239). Similar inactivation kinetics are also observed with oADP, but the kinetics of inactivation are the same whether Mg2+ is present or absent (95). The type of subunits and stoichiometry for the binding of oADP to F1 are somewhat controversial; the binding of oADP to both and β subunits with a stoichiometry of 2 to 3 mol oADP/mol F1 (95, 239) and the binding of oADP only to subunits with a stoichiometry of 0.9 to 1 mol oADP/mol F1 (217) both have been proposed. oAMP also inactivates F1, while AMP is not a substrate for F1. Finally, both oADP and oAMP inactivate F1 more efficiently than does oATP (Table 17).
Cibacron blue and 4-benzoyl(benzoyl)-1-amidofluorescein (BzAF) are structural analogs of purine nucleotides. They bind to MF1 and inhibit ATPase activity (28, 297). BzAF contains a benzophenone moiety on one side of the molecule that is excitable by irradiation at 340 to 366 nm, and the irradiation of BzaF leads to the covalent insertion of BzAF into F1. BzAF also contains a fluorescein moiety on the other side of the molecule that fluoresces at >515 nm upon excitation at 460 to 490 nm. BzAF inhibits mitochondrial ATP synthase as a catalytic site-specific covalent modifying agent (297). Like BzATP, BzAF binds to F1 competitively with respect to ATP in the absence of illumination and forms a covalent bond with F1 upon actinic irradiation. The photoinactivation of F1 by BzAF follows pseudo-first-order kinetics.
8-Azido-ATP and 8-azido-ADP are adenine-modified analogs of ATP and ADP in which an azido group is attached to the carbon 8 of adenine (Fig. 9B). 8-Azido-ATP is a substrate of F1 and is hydrolyzed slowly by F1 in the dark (420). The Km for 8-azido-ATP is similar to that for ATP, but the Vmax of hydrolysis with 8-azido-ATP is only 6% of that observed with ATP (bovine heart MF1) (371). On irradiation at 350 to 360 nm, the 8-azido-ATP inactivates F1-ATPase by binding covalently to F1, where both and β subunits are modified. About 2.5 to 3 times more 8-azido-ATP is bound to β than to subunits in MF1 (175, 371), whereas almost equal amounts are bound at these two subunits in CF1 (421). The modified residues in the β subunit of bovine heart F1 are Lys301, Ile304, and Tyr311 (175). F1-ATPase activity is completely inhibited when 2 mol 8-azido-ATP binds per mol F1. Moreover, Mg2+ is not required for the binding (420). Interestingly, 8-azido-ADP is phosphorylated by ATP synthase in SMP at a very low rate in the dark. The Ki for 8-azido-ADP is about 1 mM for mitochondrial F0F1 from bovine heart, whereas the Ki for ADP is 20 nM for MF1 from the same source (371). Photolysis at 350 nm leads to the inactivation of ATP synthase, as the 8-azido-ADP preferentially binds to β subunits (133, 371). The ATPase activity of F1 is completely inhibited at 2 mol of 8-azido-ADP bound per 1 mol F1 (419). In the presence of fluoroaluminate, 8-azido-ADP modifies βTyr-345 (133).
2-Azido-ATP and -ADP are also adenine-modified analogs of ATP and ADP in which an azido group is attached to carbon 2 of adenine. 2-Azido-ADP photolabels β subunits exclusively upon photoirradiation, in contrast to 8-azido-ADP or -ATP, which modify both and β subunits (86, 89, 419, 421). 2-Azido-ADP binds to F1 with an affinity similar to the affinity of ADP (45), and upon irradiation it modifies βLeu342, βIle344, βTyr345, βPro346, or βTyr368 (bovine heart MF1) (111, 132).
2- and 8-Azidoadenyl-5'-imidodiphosphate (2-azido-AMP-PNP and 8-azido-AMP-PNP) are derivatives of AMP-PNP. They bind to F1 at what appear to be both catalytic and noncatalytic sites (109). Under nonphotolytic conditions, 2-azido-AMP-PNP has a much higher inhibitory potency (Ki = 4 µM) than 8-azido-AMP-PNP (Ki = 460 µM).
3'-Arylazido butyryl ADP (NAP4-ADP) is a photoreactive derivative of ADP in which a photosensitive N-4-azido-2-nitrophenylaminobutyryl group is attached to the adenine ring of ADP (244). NAP4-ADP is a competitive inhibitor with respect to ATP, with a Ki value of 0.6 mM (bovine heart MF1). NAP4-ADP is a moderate inhibitor in the dark. However, upon photoirradiation with visible light, it inactivates F1 by binding covalently to both and β subunits. NAP4-AMP-PNP (or NAP4-AdoPP[NH]P) is an analog of NAP4-ATP containing an NH group that replaces oxygen at the position of the terminal bridge oxygen of the triphosphate chain. NAP4-AMP-PNP binds to F1 with high affinity, and upon illumination, it inactivates F1 by covalently modifying and β subunits (247). NAP4-AMP-PNP preferentially modifies the subunit(s) at low concentrations, whereas it modifies and β subunits equally at high concentrations.
3'-O-[3-[N-(Azido-2-nitrophenyl)amino]propionyl]ATP (NAP3-ATP) and NAP3-ADP are analogs of ATP and ADP in which a photoreactive N-4-azido-2-nitrophenylaminopropionyl group is attached to the adenine ring. NAP3-ATP acts as a substrate in the dark and shows photodependent inhibition associated with covalent modification of F1 upon illumination (117, 341). In contrast, NAP3-ADP, just like ADP, induces hysteretic inhibition of soluble F1 and membrane-bound F1, with the latter being more sensitive (117). The kinetics of inhibition is biphasic. Preincubation of MF1 from pig heart with NAP3-ADP in the dark inhibits ATPase activity about 80%, a value that is increased to 87% upon photoirradiation (117).
3'(2')-O-(2-Nitro-4-azidobenzoyl)ATP (NAB-ATP) and NAB-GTP are 3'(2')-O-(2-nitro-4-azidobenzoyl)-derivatives of ATP and GTP in which a 2-nitro-4-azidobenzoyl group is attached to the 2' hydroxyls of ribose. NAB-ATP binds to the catalytic site of F1 and is hydrolyzed to NAB-ADP and inorganic phosphate (216). After hydrolysis, NAB-ADP remains bound to F1, whereas phosphate is dissociated. The F1·NAD-ADP complex is inactive, but in the presence of ATP, the bound NAB-ADP is released, resulting in the reactivation of ATPase activity. Illumination (300 to 380 nm) of F1 inhibited with NAB-ADP leads to its covalent binding to the enzyme. NAB-GTP has an inhibitory activity similar to that of NAB-ATP.
3'-O-[3-(4-Azido-2-nitrophenyl)propionyl]-ADP (ANP-ADP) is a photoreactive analog of ADP in which a 4-azido-2-nitrophenyl propionyl group is attached to the 3' hydroxyls of ribose (Fig. 9B). ANP-ADP binds to nucleotide binding sites on F1, inhibiting both ATP hydrolysis and ATP synthesis (355, 426). Inhibition of F1 by ANP-ADP is competitive with ADP in the dark, but upon illumination, ANP-ADP inactivates F1 by covalently modifying and β subunits. The stoichiometry for complete photoinactivation of F1 is 3 mol of ANP-ADP/mol of F1. The inhibition of F1 by the photolabeling is reversed by mild alkaline treatment due to the hydrolysis of the 3'-ester bond and release of the ADP moiety of the inhibitor (426).
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Phenylglyoxal and butanedione are dicarbonylic Arg residue modifiers. They inactivate both membrane-bound and isolated F1 (Fig. 10A and Table 19) (43, 128, 129, 162, 248, 375, 381, 385). Inactivation by these agents follows pseudo-first-order kinetics (67, 128, 129, 248). Although the rate of inactivation is decreased in the presence of ADP and ATP (67, 128, 398), it is not significantly influenced by the presence of phosphate (398). Phenylglyoxal and butanedione also inhibit ATP
Pi exchange activity (43, 128, 162, 248, 385). Only one molecule of reagent per F1 active site is required for inactivation, with the binding site(s) believed to be located at or near this active site (128, 248).
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FIG. 10. Structures of amino acid residue modifiers. (A) Amino group modifiers. FDNB, 1-fluoro-2,4-dinitrobenzene. (B) Carboxyl group modifiers. CMCD, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate. (C) Cys/Tyr residue modifiers. DTNB, 5,5'-dithiobis(2-nitrobenzoic acid). (D) His residue modifiers.
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TABLE 19. Amino group modifiers
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Dansyl chloride is an acyl chloride of 5-dimethylamino-1-naphthalenesulfonic acid. It modifies reactive amino groups of proteins. Dansyl chloride binds to MF1 and inhibits both ATP synthesis and membrane-bound ATPase activity to approximately the same extent (250).
Carbodiimides are compounds containing a N=C=C functional group. Some inhibit ATP synthase by modifying carboxyl residues residing within F1, F0, or both (Fig. 10B). DCCD and N-(2,2,6,6-tetramethylpeperidyl-1-oxyl)-N-(cyclohexyl)carbo-diimide (NCCD) are lipid-soluble carbodiimides. DCCD binds to both F1 and F0 of ATP synthases from mitochondria and some bacteria (137, 204, 400, 441) (Table 20). F1 from some bacteria, such as Helicobacter pylori, are insensitive to DCCD (36). DCCD reacts covalently with DCCD-sensitive F1 via a Glu residue in the β subunit. In F1 from E. coli, βGlu192 binds DCCD, while in bovine MF1, βGlu199, corresponding to E. coli βGlu192, is modified. In F1 from thermophilic Bacillus, βGlu181 (E. coli sequence) rather than βGlu192 is modified (137, 400, 441). Incorporation of 1 mol of DCCD into 1 mol of F1 results in 95% inhibition of the ATPase activity of EF1, and 2 mol of DCCD/mol F1 leads to complete inhibition (400). In the crystal structure of the F1-DCCD complex from bovine heart mitochondria, one molecule of DCCD is bound per F1 (137). In this structure, the βGlu199 of βDP located at the interface between βDP and
DP is modified. The covalently modified DCCD (dicyclohexyl-N-acylurea) is bound in a hydrophobic cleft with one face exposed to the solvent. Residues βVal164, βMet167, βVal420 and βPhe424 contribute to the binding of DCCD, and the steric hindrance involved is believed to inhibit F1 by blocking a conformational change from βDP to βE. |
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TABLE 20. Carboxyl group modifiers
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NCCD is a lipid-soluble spin-labeled inhibitor of ATP synthase that targets the F0 of ATP synthase (23, 24). The binding site for NCCD is believed to be the same as that for DCCD, i.e., Asp61 of subunit c, as NCCD's binding to the ATP synthase is prevented by DCCD (24). Moreover, the mutant of Ala25 in subunit c, which is near Asp61, shows a greatly reduced inhibitory activity with NCCD (138).
1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate and ethyldimethylaminopropyl carbodiimide (EDC) are water-soluble carbodiimides that modify a carboxyl group(s) in F1. 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate binds to F1 reversibly and likely modifies carboxyl groups near the catalytic sites (186). EDC inhibits F1 after modifying several carboxyl groups in β subunits. The inhibition by EDC is greatly reduced by Mg2+ (236). Incorporation of about 13 mol of EDC/mol F1 (E. coli) leads to 95% inhibition of ATPase activity. Here, two-thirds of the bound EDC is bound to β subunits, where it modifies multiple sites in a short segment (residues 162 to 194) (E. coli sequence) (236). EDC also promotes formation of intersubunit cross-links between subunits β and . The residues involved are βGlu381 and likely Ser108 (90).
N-Ethoxycarboxyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) inhibits both MF1 and BF1 (Fig. 10B and Table 20) (204, 222, 250, 320, 322, 399). The inactivation by EEDQ is both pH and temperature dependent and also time and concentration dependent (204, 322). One mole of EEDQ binds to one mole of F1. The inactivation follows pseudo-first-order kinetics until 90 to 95% inactivation occurs (322). Inhibitions by EEDQ and DCCD are additive, suggesting that the binding sites of EEDQ and DCCD are either the same (204, 222) or located close to each other (320).
Woodward's reagent K inhibits both F1 and F0 (204, 381). The chemical modification of the β subunit of F1 from Rhodospirillum rubrum with this reagent results in loss of both phosphate and ATP binding capacities (203). However, ADP binding sites remain active. Chemical modification of F0 from E. coli by Woodward's reagent K inhibits both proton translocation and total ATPase activity (381).
4-Chloro-7-nitrobenzofurazan (NBD-Cl) is a fluorescent adenine analog that labels Tyr or Cys residues (Fig. 10C and Table 21). It inhibits both the synthetic and hydrolytic activities of ATP synthases from bacteria, chloroplasts, and mitochondria by modifying an essential residue (βTyr311, bovine sequence) at the catalytic site(s) of F1 (12, 70, 119, 120, 245, 388, 415). Depending on the experimental conditions, other subunits, particularly the
subunit, are also modified by NBD-Cl (96, 121, 146, 283). In F1 modified by NBD-Cl, the Tyr-O-NBD linkage is unstable at alkaline pH. The NBD group from βTyr311 migrates to βLys162 in the P-loop at pH 9 as a consequence of O-to-N migration (13, 14, 121). The resulting NBD-N-Lys derivative of F1 is also catalytically inactive (14, 121). In a crystal structure of bovine MF1 covalently modified by NBD-Cl, the NBD-Cl is found in only one of three β subunits, βE (292). The βTyr311 residues in the βTP and βDP subunits are buried at the -β subunit interfaces and are inaccessible to NBD-Cl. The NBD binding pocket is positioned in the central nucleotide binding domain with no hydrogen bonds between the NBD ring and the protein. NBD-Cl appears to inhibit F1 by preventing βE from undergoing a conformational change (292). |
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TABLE 21. Cys/Tyr residue modifiers
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Thiol group reagents, N-ethylmaleimide (NEM), bismuth subcitrate, omeprazole, 5,5'-dithiobis(2-nitrobenzoic acid), p-chloromercuribenzoate (PCMB), p-chloromercuribenzene sulfonate (PCMS), mersalyl, 2,2'-dithiobispyridine, and N-(7-dimethylamino-4-methyl-coumarinyl)-maleimide inhibit ATP synthase by modifying Cys residues. Specifically, NEM inhibits the ATPase activity of F1s from fungi, some bacteria such as Vibrio parahaemolyticus, and some mitochondria, i.e., those from S. cerevisiae and Schizosaccharomyces pombe (115, 145, 344). The inactivation of F1 by NEM in sensitive cases is irreversible and protected by nucleotides (115). In contrast, the F1s from E. coli and bovine heart mitochondria are resistant to NEM (344, 366). NEM also binds various F0 polypeptides, inhibiting proton conduction (445). For example, NEM inhibits mitochondrial F0 from bovine heart while labeling 25-, 11-, and 9-kDa polypeptides (445).
Bismuth subcitrate and omeprazole are antiulcer drugs. They bind to sulfhydryl groups of F1 and form stable complexes (36). They inhibit the ATPase activity of F1 from Helicobacter pylori via a reaction that can be prevented and also reversed by mercaptan glutathione. At low pH, omeprazole is converted into a cyclic sulfonamide, and this form inhibits the ATPase activity of H. pylori F1 more potently than the form without acid activation (I50 = 43 µM when acid activated, compared to 90 µM without acid activation).
Regarding other sulfhydryl reactive agents, 5,5'-dithiobis(2-nitrobenzoic acid) inhibits the ATPase activity of nucleotide-depleted F1 (392). In contrast, it is inhibitory neither to native F1 nor to nucleotide-depleted F1 in the presence of either ADP or ATP.
PCMB, PCMS, and mersalyl are polar organic mercurials that target F0 of mitochondrial ATP synthase. Both PCMB and PCMS inhibit the ATP synthesis and ATPase activities of bovine heart ATP synthase. Thiols modified by the mercurials are different from those modified by NEM (438). In contrast to the case for NEM, inhibition by mercurials is reversed almost completely (PCMB) or partially (PCMS) by addition of dithiothreitol. Moreover, the binding of mercurials protects the ATP synthase from irreversible inhibition by DCCD. Mersalyl also inhibits proton conductivity by F0 from bovine heart mitochondria. Here, the inhibition is much more potent than that observed with PCMB and PCMS (445). Although mersalyl has no inhibitory effect at concentration of up to 
50 µM, it inhibits proton conduction at higher concentrations (70% inhibition at 130 µM).
The sulfhydryl-reactive agents 2,2'-dithiobispyridine and N-(7-dimethylamino-4-methyl-coumarinyl)-maleimide also inhibit proton conductivity by F0 from bovine heart mitochondria (445). N-(7-Dimethylamino-4-methyl-coumarinyl)-maleimide has stronger inhibitory potencies than 2,2'-dithiobispyridine and NEM. N-(7-dimethylamino-4-methyl-coumarinyl)-maleimide shows no inhibition up to a concentration of 200 µM and inhibits proton conduction by 60% at 400 µM.
Diethyl pyrocarbonate and Rose bengal are His residue-modifying reagents (Fig. 10D and Table 22). Diethyl pyrocar-bonate modifies the ATP synthase β subunit, completely preventing the binding of phosphate. It also blocks the binding of ATP to a Mg2+-dependent low-affinity site (203, 381, 445). In contrast, the ADP binding capacity of the β subunit is not affected by modification with diethyl pyrocarbonate (203). Diethyl pyrocarbonate also modifies F0 from E. coli, inducing inhibition of proton uptake (381).
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TABLE 22. His and other amino acid residue modifiers
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Iodine is an electron-dense heavy atom that reacts with and inactivates F1 (314). It behaves like a typical covalent inhibitor in its modification of amino acid residues. MgATP, MgADP, and phosphate fail to protect F1 from inhibition by iodine. Iodine preferentially labels the ATP synthase β subunit, although it also labels
and subunits to some extent. About 10 atoms of iodine are incorporated per F1 (rat liver mitochondria) under conditions where the labeling proceeds in a linear fashion. About two atoms of iodine are incorporated per β subunit. |
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High hydrostatic pressure of above 60 to 80 MPa inactivates both F1 and the complete ATP synthase (F0F1) (Table 23) (105, 310, 377). At below 60 to 80 MPa, the hydrostatic pressure shows stimulatory effects on ATPase activity. However, both membrane-bound and isolated F0F1 from mitochondria are inhibited reversibly at high hydrostatic pressure, while soluble F1-ATPase is inactivated irreversibly due to reassociation with an altered hydrodynamic radius after decompression (105). In contrast to the case for the isolated mitochondrial ATP synthase, the inhibition of the isolated ATP synthase from chloroplasts is irreversible, showing no restoration after decompression (377). The inactivation is dependent on protein concentration (377). Inhibition by high hydrostatic pressure is believed to be associated with dissociation that impairs contacts essential for transmission of conformational information between those subunits needed for rotational catalysis (105, 377).
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TABLE 23. Physical inhibitory factors
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Mitochondrial ATPase activity is inhibited also by far-UV irradiation. UV light at 254 nm results in a time-dependent inhibition of both membrane-bound and soluble F1. Inhibition reaches its maximum level within 15 min after exposure of SMP to UV (75). This also induces the release of tightly bound adenine nucleotides from F1. Succinate, a substrate for the electron transport chain, partially protects against the detrimental effects of UV. Inhibition by UV is due to the photochemical modification of the essential Tyr residue located at the active site of F1 that induces subsequent structural changes in F1.
The F1"catalytic" moiety of the ATP synthase (F0F1) is cold labile (308, 309, 324). Its ATPase activity decrease rapidly upon incubation at low temperature. The rate of inactivation is first order, and the half-life varies between 15 and 60 min with different preparations (324). The inactivation is not protected by ATP, ADP, or Mg2+ and is reversed by rewarming the enzyme solution under appropriate conditions (309). The inactivation by cold temperature is associated with the dissociation of the enzyme complex into subunits (309).
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Polyborates are boron cluster compounds with a unique molecular structure and unusual chemical properties. Among the polyborates, dodecaborates ([B12H12]2–) and dicarbononaborates ([C2B9H11]–) inhibit ATPase activity of MF1, and dicarbononaborates have much stronger inhibitory potencies than dodecaborates (Fig. 11) (104). One of the dicarbononaborates, dichlorodicarbononaborate ([Cl2C2B9H10]–), that contains two chlorides inhibits competitively with respect to ATP the ATPase activities of both membrane-bound and soluble F1. The inhibition is due to a direct interaction of the reagent with the catalytic F1 moiety (104).
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FIG. 11. Miscellaneous inhibitors. TCS, tetrachlorosalicylanilide.
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5-Hydroxynaphthalenedicarboxylic anhydride (HNA) inhibits the mitochondrial ATPase activity induced by 2,4-dinitrophenol and the ATPase activity of SMP induced by Mg2+ (165). HNA also inhibits the ATP-energized mitochondrial volume change. The inhibitory effects of HNA are similar to those of rutamycin.
R207910 is a diarylquinoline drug that has antimycobacterial activity. It inhibits mycobacterial ATP synthase and targets subunit c in F0 (15, 215, 313). The site of action of R207910 seems to be located close to an essential carboxyl residue, Asp61 of subunit c (E. coli sequence), as the mutations Asp32Val (Mycobacterium smegmatis) and Ala63Pro (M. tuberculosis) confer resistance to the drug. Also, the mycobacterial species naturally resistant to R207910 contains Met at position 63 in place of a conserved Ala in all sensitive mycobacteria (15, 181, 313). R207910 is an enantiomeric compound with two chiral centers. It adopts the lowest-energy conformation with the carbon alpha relative to the quinoline moiety R and the carbon beta S (135). The binding of the inhibitor to the binding site in ATP synthase is stereoselective, and its (S,R) stereoisomer is 2 orders of magnitude less inhibitory than R207910 (215). R207910 appears to act specifically on mycobacteria, and the range of MICs of R207910 is 0.03 to 0.12 µg/ml for 99% inhibition of the growth of M. tuberculosis strains (15). The killing effect of M. tuberculosis by R207910 is time dependent rather than concentration dependent (15), and R207910 acts synergically when combined with other tuberculous drugs (183, 237, 238).
Spegazzinine is a dihydroindole alkaloid from Aspidosperma chakensis Spegazzini (103). It inhibits uncompetitively the ATPase activities of both membrane-bound and isolated CF1 from spinach (10). Spegazzinine inhibits both cyclic and noncyclic photophosphorylation of isolated spinach chloroplasts. It also inhibits the mitochondrial ATPase activity of S. pombe (234) and slightly inhibits the mitochondrial ATPase activity of Tetrahymena pyriformis ST (404). In contrast, spegazzinine has no inhibitory effects on the ATPase activities of ATP synthases from Clostridium pasteurianum (78), Tritrichomonas foetus (235), and mitochondria of Crithidia fasciculata (439).
n-Butanol inhibits the ATPase activities of both membrane-bound and soluble MF1 (406). It inhibits the isolated F1 at the same or lower concentrations as it inhibits membrane-bound F1. Inhibition is temperature dependent. N-Butanol also shows partial inhibition of ATP synthesis.
Tetrachlorosalicylanilide is a lipophilic weak acid known as an H+ conductor. It inhibits the ATPase activities of both isolated F1 and F0F1 from Vibrio parahaemolyticus (290, 344). The concentration of tetrachlorosalicylanilide for 50% inhibition of F0F1-ATPase activity from V. parahaemolyticus is about 9 to 10 µM (290).
Dihydrostreptomycin is a polycationic aminoglycoside antibiotic drug produced from Streptomyces humidus. It significantly stimulates the ATPase activity of membrane-bound ATP synthase from bovine heart mitochondria in the concentration range of 1 to 5 mM. The stimulation is followed by inhibition at higher concentrations (161). Dihydrostreptomycin also inhibits the ATPase activity of isolated F1, but the stimulation of the ATPase activity observed in the inhibition of membrane-bound F1 at low concentrations of dihydrostreptomycin is not observed in the inhibition of isolated F1. The inhibition of ATPase activity of F1 by dihydrostreptomycin is noncompetitive. Dihydrostreptomycin also exhibits partial inhibition of proton conductivity of F0 in the ATP synthase devoid of its catalytic F1 moiety.
Suramin, a synthetic antiparasitic drug, is an inhibitor of various proteins in different cell types and also inhibits the binding of some growth factors to their receptors. Suramin also binds to ATP synthase and inhibits both F1-ATPase and membrane-bound F0F1-ATPase from mitochondria (28, 173). Suramin acts as a noncompetitive inhibitor of the membrane-bound ATPase and as a strictly competitive inhibitor of purified F1-ATPase (173). Half-maximal inhibition of rat liver F1-ATPase occurs at 40 µM suramin.
Bz-423 is an 1,4-benzodiazepine derivative known as a cytotoxic immunomodulatory drug that suppresses disease in lupus-prone mice by inducing apoptosis in autoreactive B and T lymphocytes (193). Bz-423 binds to the OSCP subunit of ATP synthase and inhibits both synthetic and hydrolytic activities of the enzyme. The inhibition of the ATPase activity of ATP synthase by Bz-423 leads to rapid generation of superoxide (O2–) from the respiratory chain within mitochondria and the initiation of apoptosis by the reactive oxygen species. Bz-423 affects both the Vmax and Km of the ATPase activity of ATP synthase and inhibits ATP synthesis in a concentration-dependent fashion.
Dimethyl sulfoxide (DMSO) inhibits the hydrolytic activities of BF1 and MF1 strongly at concentrations of above 30 to 40% (9, 345, 440). Inhibition by DMSO is reversible, affecting Vmax without a significant change in the Km (9, 440). In contrast, the synthesis of ATP by soluble F1 is promoted in the presence of DMSO (94, 197, 346). The effect of DMSO on the promotion of ATP synthesis by isolated F1 is considered to be due to an increase in affinity of F1 for phosphate at the catalytic site (197, 345).
Hypochlorous acid (HOCl) is a strong oxidant that is produced as a microbicide in activated neutrophils and monocytes by myeloperoxidase-catalyzed peroxidation of chloride ion (182). HOCl inhibits the ATPase activity of F1 in a biphasic fashion. The ATPase activity falls rapidly to 20 to 30% at low concentrations of HOCl and then slowly to zero at high concentrations (29). The biphasic mode of inhibition is attributed to two different inhibitory activities of HOCl: oxidative modification of intact F1 and subunit dissociation of F1 due to more extensive oxidation (29, 167). The target sites for HOCl are believed to be amino acid residues within nucleophilic side chains (167).
4,4'-Dichlorodiphenyltrichloroethane (DDT) is a synthetic organic insecticide and affects sodium ion channels in the neurons of DDT-sensitive insects, causing repetitive discharge by the increase and prolongation of membrane's negative after-potential, leading to spasms and eventual death. DDT binds to an unidentified 23-kDa protein in the F0 of mitochondrial ATP synthase and inhibits the ATPase activity of the enzyme (442, 443). The 23-kDa protein is present in DDT-sensitive insects but not in DDT-tolerant insects and mammals, and the prepared DDT-sensitive ATP synthase devoid of the 23-kDa protein is not inhibited by DDT (442, 443).
Diazoxide, a mitochondrial potassium channel activator, is a cardioprotective drug for short-term treatment of malignant hypertension. Diazoxide also binds to MF1 and potentiates the binding of IF1 to F1, inhibiting the ATPase activity of ATP synthase (79, 80). The inhibition by diazoxide is reversible, and the binding of one equivalent of diazoxide to F1 is sufficient to inhibit the F1-ATPase activity. The inhibitory effect of diazoxide is ATP dependent, and no inhibition is observed without Mg2+-ATP. The binding site of diazoxide is believed to be located within the nucleotide binding domain of the β subunit.
2-Hydroxy-5-nitrobenzyl bromide (HNB) stimulates the hydrolytic activity of F1 from bovine heart mitochondria at below 0.5 mM but exhibits a concentration-dependent inhibition of F1 from the same source at above 0.5 mM (26, 27). HNB is a Trp-modifying reagent. Its capacity to activate catalytic activity at below 0.5 mM is attributed to its covalent interaction with a single Trp residue in the subunit of F1 (26). In contrast, HNB's inhibitory effect at above 0.5 mM appears to be due to noncovalent, reversible, aspecific binding to F1. About 50% of the hydrolytic activity is inhibited at 2.5 mM.
A series of derivatives of benzodiazepine, 4-(N-arylimidazole)-substituted benzopyran, and N-[1-aryl-2-(1-imidazolo)ethyl]-guanidine have been synthesized and tested for the treatment of ischemic heart disease as cardioprotective agents (Table 24) (20, 21, 166). During ischemia, ATP is hydrolyzed by mitochondrial ATP synthase, leading to depletion of ATP. To prevent the ATP wastage in ischemia, the ATPase activity of ATP synthase should be inhibited selectively without affecting the ATP synthesis activity of the enzyme. Several inhibitors were proposed as potential compounds for drug design for ischemia.
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TABLE 24. Miscellaneous inhibitors
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4-(N-Arylimidazole)-substituted benzopyran derivatives are inhibitors of ATP hydrolysis of mitochondrial ATP synthase (21, 156). The inhibition of ATP synthesis by these derivatives is about an order of magnitude less potent than that of ATP hydrolysis (21). Both the N-arylimidazole ring and benzopyran seem to be required for inhibition, since the removal of either from the structure causes a dramatic loss of inhibitory potency. BMS-199264 has been tested as a cardioprotective agent in ischemic rat hearts and showed selective inhibition of ATP hydrolase activity with no effect on ATP synthesis (156). It conserved ATP during ischemia, while it had no influence on preischemic ATP concentrations and cardiac function.
Cyano- and acylguanidine derivatives containing imidazoloethyl and aryl groups also inhibit the hydrolytic activity of mitochondrial ATP synthase (20). Inhibition by derivatives of N-[1-aryl-2-(1-imidazolo)ethyl]-cyanoguanidine and N-[1-aryl-2-(1-imidazolo)ethyl]-acylguanidine is selective for ATPase activity. No inhibition of ATP synthesis is observed up to 100 µM. In cyanoguanidine derivatives, the number and position of the chloride in aryl groups are believed to be important for their inhibitory activities. For example, the 2,4-dichloro analog is more potent than 2,3-dichloro and monochloro analogs in inhibiting the ATPase activity of F1. Two symmetrical enantiomers with an identical chemical composition also have different inhibitory potencies. For instance, one entiomer of N-[(Z)-[(4-chlorophenyl)amino]{[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]amino}methylidene]-3-cyanobenzamide inhibits the ATPase activity of bovine mitochondrial ATP synthase (F0F1) with an I50 of 18 nM, whereas the other entiomer has no inhibitory activity on the ATPase activity of the same enzyme (20).
O-[1-Aryl-2-(1-imidazolo)ethyl]-thiourethane derivatives also inhibit the ATPase activity of mitochondrial ATP synthase. Similar to the derivatives of N-[1-aryl-2-(1-imidazolo)ethyl]-cyanoguanidine and N-[1-aryl-2-(1-imidazolo)ethyl]-acylguanidine, the O-[1-aryl-2-(1-imidazolo)ethyl]-thiourethane derivatives also maintain selectivity for inhibition of ATPase activity of ATP synthase over ATP synthesis. For example, substitutions in the 1-aryl-2-imidazoloethyl and aniline moieties affect the inhibitory potencies of the derivatives, and halogen substitution in these moieties also seems to be favorable for promoting inhibition.
Dio-9 is a mixture of at least nine compounds, two of which have antibiotic properties (232). Dio-9 inhibits both ATPase and ATP synthase activities of mitochondria, chloroplasts, and bacteria (124, 125, 163, 169, 431). There is still much to be learned about the structures and chemical actions of the class of compounds comprising Dio-9.
Ethanol inhibits the ATPase activity of F0F1 from V. parahaemolyticus at concentrations of above 4% (290). In contrast, ethanol exhibits stimulatory effects on the ATPase activity of F1.
Zinc strongly inhibits the ATPase activities of both purified and membrane-bound F0F1 from V. parahaemolyticus (267, 290). The site of action of the zinc ion is considered to be located within F0 (290).
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ATP synthase was previously considered to be located only in the mitochondrial inner membrane, the bacterial plasma membrane, and the chloroplast thylakoid membrane. It was also considered to be involved only in the synthesis of ATP or in the generation of a proton gradient. Now, however, significant evidence has accumulated that the ATP synthase is also present on the surfaces of multiple animal cell types and serves as a receptor for various ligands, participating in a number of cellular processes, including angiogenesis, lipid metabolism, the regulation of intercellular pH, and the cytolytic pathway of tumor cells (17, 38, 39, 72, 91, 202, 269). As the multiple roles of the cell surface ATP synthase are now beginning to be understood, this pivotal enzyme complex both at this location and its mitochondrial location is emerging as a molecular target for the treatment of various diseases.
The use of ATP synthase as a molecular target has multiple advantages. First, as it is indispensable for energy metabolism, if selectively targeted, it may be possible to eradicate some types of cancer. It may also provide an ideal target for controlling a number of other diseases because of its complex subunit composition. For example, it has been demonstrated already that a lupus drug, Bz-423, targets the OSCP of F0, whereas an antimycobacterial drug, R207910, binds to subunit c of F0 (15, 193, 313). In addition, it has been shown that resveratrol and piceatannol, potential antiangiogenesis agents, block tumor growth by binding to the β subunit of F1 (143, 449). Lastly, the high inhibitory specificity of ATP synthase inhibitors also suggests that this complex is an excellent target for the development of new insecticidal or herbicidal agents. For example, tentoxin is a strong inhibitor of CF1-ATPase from certain sensitive species such as spinach, potato, and lettuce, but it has little or no inhibitory effect on the same enzyme from insensitive species such as corn, tobacco, and radish, even though they exhibit high sequence and structural similarity (380). In addition, slight structural modifications of tentoxin can cause dramatic effects on the properties and inhibitory potencies of the inhibitor (316, 351). Finally, the drug R207910, developed for the treatment of tuberculosis, also shows a narrow selectivity in its inhibition of the ATP synthase in mycobacterial species (15).
The mitochondrial ATP synthase contains a number of supernumerary subunits that are absent in bacterial or chloroplast counterparts. The plasma membrane ATP synthase found in various types of animal cells also includes more subunit types than the bacterial and chloroplast ATP synthases. The roles of the supernumerary subunits are currently unknown or poorly defined, but evidence is accumulating that these "extra" subunits are also involved in cellular processes other than ATP synthesis. Thus, subunit F6 has been reported to be associated with regulating blood pressure. Additionally, subunit e has been reported to be involved in the regulation of the expression of the gene for subunit g of the ATP synthase (18) and also for that of the c-myc proto-oncogene (177, 226). The expression level of subunit e has also been shown to be highly sensitive to diverse physiologic changes and stresses. Although the detailed regulatory roles of subunits F6 and e and the roles of other supernumerary subunits require further investigation, it seems likely that they will be implicated in a multitude of cellular processes that will result in future use of the ATP synthase as a drug target.
In this review, we have provided detailed information about most natural and synthetic inhibitors of ATP synthases reported to date. Figure 12 summarizes the known or proposed sites of these ATP synthase inhibitors. About 270 inhibitors are described here and need further investigations to identify clearly or confirm their sites of actions and inhibitory mechanisms. When this mammoth task is accomplished, it will further heighten consideration of ATP synthase as a major target for new therapies for human and animal diseases and likely contribute also to the discovery of novel agents that may prove valuable in agriculture and other areas. In addition, the rich source of structures and other knowledge about ATP synthase inhibitors already provided in this review will likely prove invaluable as scaffolds for new drug discoveries in the near future.
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FIG. 12. Inhibitory sites of ATP synthase. The inhibitor binding sites in the ATP synthase as revealed by biochemical/structural studies are indicated by red circles, and the binding subunits in which the binding sites have not been completely clarified are indicated by green circles. The coordinates of each subunit in the structural model are the same as in Fig. 1.
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P.L.P. is supported for work on ATP synthase by National Institutes of Health grants 5R01 CA10951 and 5P01 HL081427.
* Corresponding author. Mailing address: Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205-2185. Phone: (410) 955-3827. Fax: (410) 614-1944. E-mail: ppederse{at}jhmi.edu
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