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Microbiology and Molecular Biology Reviews, September 2009, p. 510-528, Vol. 73, No. 3
1092-2172/09/$08.00+0     doi:10.1128/MMBR.00001-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cytochrome c Biogenesis: Mechanisms for Covalent Modifications and Trafficking of Heme and for Heme-Iron Redox Control

Robert G. Kranz,1* Cynthia Richard-Fogal,1 John-Stephen Taylor,2 and Elaine R. Frawley1

Department of Biology,1 Department of Chemistry, Washington University, One Brookings Dr., St. Louis, Missouri 631302

Summary: Heme is the prosthetic group for cytochromes, which are directly involved in oxidation/reduction reactions inside and outside the cell. Many cytochromes contain heme with covalent additions at one or both vinyl groups. These include farnesylation at one vinyl in hemes o and a and thioether linkages to each vinyl in cytochrome c (at CXXCH of the protein). Here we review the mechanisms for these covalent attachments, with emphasis on the three unique cytochrome c assembly pathways called systems I, II, and III. All proteins in system I (called Ccm proteins) and system II (Ccs proteins) are integral membrane proteins. Recent biochemical analyses suggest mechanisms for heme channeling to the outside, heme-iron redox control, and attachment to the CXXCH. For system II, the CcsB and CcsA proteins form a cytochrome c synthetase complex which specifically channels heme to an external heme binding domain; in this conserved tryptophan-rich "WWD domain" (in CcsA), the heme is maintained in the reduced state by two external histidines and then ligated to the CXXCH motif. In system I, a two-step process is described. Step 1 is the CcmABCD-mediated synthesis and release of oxidized holoCcmE (heme in the Fe+3 state). We describe how external histidines in CcmC are involved in heme attachment to CcmE, and the chemical mechanism to form oxidized holoCcmE is discussed. Step 2 includes the CcmFH-mediated reduction (to Fe+2) of holoCcmE and ligation of the heme to CXXCH. The evolutionary and ecological advantages for each system are discussed with respect to iron limitation and oxidizing environments.

* Corresponding author. Mailing address: Department of Biology, Campus Box 1137, Washington University, One Brookings Dr., St. Louis, MO 63130. Phone: (314) 935-4278. Fax: (314) 935-4432. E-mail: kranz{at}biology.wustl.edu

Microbiology and Molecular Biology Reviews, September 2009, p. 510-528, Vol. 73, No. 3
1092-2172/09/$08.00+0     doi:10.1128/MMBR.00001-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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