C-type cytochromes are a structurally diverse group of haemoproteins, which are related by the occurrence of haem covalently attached to a polypeptide via two thioether bonds formed by the vinyl groups of haem and cysteine side chains in a CXXCH peptide motif. Remarkably, three different post-translational systems for forming these cytochromes have been identified. The evolution of both the proteins themselves and the biogenesis systems poses many questions to which answers are currently being sought. In this article we review the progress that has been made in understanding the need for covalent attachment of haem to proteins in cytochromes c and the complex systems involved in their formation.
C-type cytochromes are essential for almost all organisms; they are characterized by the covalent attachment of heme to protein through two thioether bonds to a Cys-Xaa-Xaa-Cys-His peptide motif. Here we show, contrary to opinion of 30 years standing, that a c-type cytochrome can form from heme and apoprotein in vitro under mild conditions and in the absence of any biosynthesis apparatus. This reaction occurs provided formation of a disulfide bond within the Cys-Xaa-Xaa-Cys-His motif is avoided. There are important implications for understanding in vivo cytochrome c assembly.
Mitochondrial cytochromes c and c1 are present in all eukaryotes that use oxygen as the terminal electron acceptor in the respiratory chain. Maturation of c‐type cytochromes requires covalent attachment of the heme cofactor to the protein, and there are at least five distinct biogenesis systems that catalyze this post‐translational modification in different organisms and organelles. In this study, we use biochemical data, comparative genomic and structural bioinformatics investigations to provide a holistic view of mitochondrial c‐type cytochrome biogenesis and its evolution. There are three pathways for mitochondrial c‐type cytochrome maturation, only one of which is present in prokaryotes. We analyze the evolutionary distribution of these biogenesis systems, which include the Ccm system (System I) and the enzyme heme lyase (System III). We conclude that heme lyase evolved once and, in many lineages, replaced the multicomponent Ccm system (present in the proto‐mitochondrial endosymbiont), probably as a consequence of lateral gene transfer. We find no evidence of a System III precursor in prokaryotes, and argue that System III is incompatible with multi‐heme cytochromes common to bacteria, but absent from eukaryotes. The evolution of the eukaryotic‐specific protein heme lyase is strikingly unusual, given that this protein provides a function (thioether bond formation) that is also ubiquitous in prokaryotes. The absence of any known c‐type cytochrome biogenesis system from the sequenced genomes of various trypanosome species indicates the presence of a third distinct mitochondrial pathway. Interestingly, this system attaches heme to mitochondrial cytochromes c that contain only one cysteine residue, rather than the usual two, within the heme‐binding motif. The isolation of single‐cysteine‐containing mitochondrial cytochromes c from free‐living kinetoplastids, Euglena and the marine flagellate Diplonema papillatum suggests that this unique form of heme attachment is restricted to, but conserved throughout, the protist phylum Euglenozoa.
C-type cytochromes are proteins that are essential for the life of virtually all organisms. They characteristically contain heme that is covalently attached via thioether bonds to two cysteines in the protein. In this Account, we describe the challenging chemistry of thioether bond formation and the surprising variety of biogenesis systems that exist in nature to perform the difficult posttranslational heme attachment process. We show what insight has been gained into the various biogenesis systems from in vitro and in vivo experiments and highlight some forthcoming challenges in this field.
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