DOI: 10.1128/MMBR.00028-07
Article Figures & Data
Figures
- FIG. 1.
Diagram of the basic components of the mycobacterial cell wall. MAPc, MA-AG-PG complex.
- FIG. 2.
Synthesis of PG. Major steps are shown, with precursors such as UDP-NAM, lipid I, and lipid II being synthesized within the cytoplasm. Lipid II is then transported across the lipid membrane, and periplasmic transglycosylases and endopeptidases link the PG monomer into existing PG sheets through β-1,4 glycosidic linkages and DAP-DAP peptide cross-linkages.
- FIG. 3.
Localization of nascent and inert PG in different bacteria.
- FIG. 4.
V-snapping process of mycobacteria during cell division.
- FIG. 5.
Cycle of mycobacteria entering and exiting dormancy. Environmental conditions and proteins thought to be involved with inducing transitions between the two life cycle stages are listed.
Tables
- TABLE 1.
Attributes of mycobacterial PG and their biological significance
Mycobacterial PG attribute Common PG attribute in other bacteria Biological significance DAP-DAP and DAP-Ala peptide cross-linkage DAP-Ala peptide cross-linkage May provide increased rigidity to the PG to help survive stressful conditions N-Glycoylmuramic acid and NAM NAM Could tighten the PG sacculus by providing more opportunities for hydrogen bonding and increase resistance to β-lactams and lysozyme Amidated l-Glu and DAP Amidated l-Glu and DAP May play a role in the regulation of cross-linking and could increase resistance to hydrolysis by specific endopeptidases, as seen with the amidation of PG sugar residues increasing resistance to muramidase d-Glutamate or l-alanine modified with glycine No modification Unknown - TABLE 2.
Bacterial cytoskeletal elements
Cytoskeletal element Protein Function M. tuberculosis homologue(s) Tubulin FtsZ Forms a structural ring that recruits proteins necessary for the synthesis of septal PG FtsZ (Rv2150c) Actin MreB (Mbl, MreBH) Cell shape, guides PG synthesis None ParM DNA partitioning ParA (Rv3918c), ParB (Rv3917c) MamK Organelle positioning ? Intermediate filament CreS Determines the specialized crescent shape None - TABLE 3.
Divisome proteins encoded in different bacterial genomes
Divisomea Function Homologueb in: E. coli B. subtilis S. coelicolor M. tuberculosis FtsA Positive regulator of FtsZ assembly, membrane associated, actin like + + − − FtsB Bridge cytoplasmic with periplasmic, transmembrane, forms tripartite complex with FtsL and FtsQ + DivIC DivIC ? FtsE Unknown, ABC transporter family + + − + FtsI Synthesize septal PG, transpeptidase (PBP 3) + + + + FtsK DNA partitioning, large multifunctional membrane protein + SpoIIIE + + FtsL Bridge cytoplasmic with periplasmic, transmembrane, forms tripartite complex with FtsB and FtsQ + + + − FtsN Unknown, weak homology to amidase, binds PG + − − − FtsQ Bridge cytoplasmic with periplasmic, many protein-protein interactions, transmembrane + DivIB + + FtsW Predicted transporter of PG precursors, multitransmembrane protein + + + Interacts with FtsZ and FtsI and may substitute for lack of ZipA or FtsA FtsX Unknown, ABC transporter family + ? − + FtsZ Initiates Z ring, helps constrict ring, tubulin like, GTPase + + + + ZipA Positive regulator of FtsZ assembly, membrane associated + ZapA − − AmiC Separates daughter cells by hydrolyzing septal PG, amidase + ? ? ? EnvC Separates daughter cells by hydrolyzing septal PG, hydrolase + ? ? ? - TABLE 4.
Inhibitors of FtsZ assembly
Inhibitor Function Homologuea in: E. coli B. subtilis S. coelicolor M. tuberculosis EzrA Negative regulator of FtsZ assembly, topology similar to that of ZapA ? + ? − MinC Negative regulator of FtsZ assembly at poles, binds and oscillates between poles with MinD + + − − MinD Oscillates MinC from pole to pole, ATPase, binds to membrane until MinE stimulates ATP hydrolysis + + − − MinE Sweeps MinCD complex from one pole to the other, stimulates MinD ATPase and release of MinCD from membrane + DivIVA; rather than oscillating between poles, remains at poles, tethering MinCD complex DivIVA DivIVA orthologue, Ag84, encoded by wag31 SulA Negative regulator of FtsZ assembly, induced by SOS response + YneA, structurally unrelated to SulA but functionally similar ? − SepF Unknown, interacts with FtsZ and localization depends on FtsZ ? + ? ? SlmA Negative regulator of FtsZ assembly, prevents septum assembly over nucleoid (nucleoid occlusion) + − ? ? Noc Negative regulator of FtsZ assembly, prevents septum assembly over nucleoid (nucleoid occlusion) ? + ? ? CrgA Negative regulator of FtsZ assembly − − + + (Rv0011c) ↵ a +, present in genome; −, not found in genome; ?, other homologues may exist.
- TABLE 5.
Mycobacterial growth regulatory systems
Growth regulatory system(s) Mechanism Mycobacterial protein(s) Function STPKs Sensors of environmental signals that regulate host-pathogen interactions and developmental changes through signal transduction using reversible phosphorylation of proteins; M. tuberculosis encodes 12 STPKs PknA Regulates cell shape; essential; transmembrane PknB Regulates cell shape; essential; transmembrane PknF Phosphorylates putative ABC transporter of M. tuberculosis (Rv1747); transmembrane PknG Modulates macrophage response to infection; essential; soluble PknH Phosphorylates the OmpR-like EmbR transcription factor; transmembrane PknK Soluble PknC, -D, -E, -I, -J, -L Transmembrane WhiB genes Thought to bind DNA and influence transcription as well as play a role in sensing intracellular redox state; M. tuberculosis encodes 7 WhiB homologues WhiB2 Possibly involved in cell wall remodeling and cell division WhiB3 Interacts with RpoV and is important for pathogenesis within the host WhiB4 May be a sensor of oxidative stress WhiB1, -5, -6, -7 Unknown TCSs Transfers a phosphate from the histidine residue on the autophosphorylated sensor to the aspartate residue on the response regulator to relay signals from the environment; M. tuberculosis encodes 11 TCSs in total (some not listed) DosRS/T Dormancy survival MtrAB Proliferation in macrophages SenX3-RegX3 May regulate phosphate-dependent gene expression MprAB Growth during persistent stage PhoPR Implicated in regulating production of complex cell wall lipids Alternative sigma factors The largest subset are known as ECF sigma factors and are small regulatory proteins lacking some of the conserved regions of typical sigma factors; M. tuberculosis encodes 13 sigma factors, 10 of which are ECF sigma factors (some not listed) SigB, -D, -E, -H Regulate genes that allow bacteria to adapt to stress TA system Originally recognized as a mechanism for ensuring proper plasmid segregation, the TA loci have now been shown to have diverse roles; works by production of a stable toxin and an unstable antitoxin, thus requiring a constant supply of antitoxin; M. tuberculosis has 38 TA loci (some not listed) 3 RelBE homologues and 9 MazEF homologues Toxins that cleave mRNA in response to nutrient stress or starvation Stringent response RelA is triggered by uncharged tRNAs at the ribosomal A site during carbon starvation and synthesizes P4G, which binds RNA polymerase, reducing the promoter open-complex half-life and halting translation RelA Synthesizes P4G SpoT Hydrolyzes P4G
