Cytochromes ''c'' (cyt ''c'', c-type cytochromes) cytochromes, or

heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...

-containing

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s, that have heme C covalently attached to the peptide backbone via one or two

thioether In organic chemistry, a sulfide (British English sulphide) or thioether is an organosulfur functional group with the connectivity as shown on right. Like many other sulfur-containing compounds, Volatile organic compound, volatile sulfides have ...

bonds. These bonds are in most cases part of a specific Cys-X-X-Cys- His (CXXCH) binding motif, where X denotes a miscellaneous

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

. Two thioether bonds of cysteine residues bind to the

vinyl Vinyl may refer to: Chemistry * Polyvinyl chloride (PVC), a particular vinyl polymer * Vinyl cation, a type of carbocation * Vinyl group, a broad class of organic molecules in chemistry * Vinyl polymer, a group of polymers derived from vinyl ...

sidechains of heme, and the histidine residue coordinates one axial binding site of the heme

iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...

. Less common binding motifs can include a single thioether linkage, a lysine or a methionine instead of the axial histidine or a CX_nCH binding motif with n>2. The second axial site of the iron can be coordinated by amino acids of the protein, substrate molecules or

water Water is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...

. Cytochromes ''c'' possess a wide range of properties and function as electron transfer proteins or catalyse chemical reactions involving redox processes. A prominent member of this family is mitochondrial cytochrome c.

Classification

Cytochrome ''c'' proteins can be divided in four classes based on their size, number of heme groups and reduction potentials:

Class I

Small soluble cytochrome ''c'' proteins with a

molecular weight A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

of 8-12 kDa and a single heme group belong to class I. It includes the low-spin soluble cytC of mitochondria and bacteria, with the heme-attachment site located towards the

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

, and the sixth ligand provided by a

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...

residue about 40 residues further on towards the C-terminus. The typical class I fold contains five α-helices. On the basis of sequence similarity, class I cytC were further subdivided into five classes, IA to IE. Class IB includes the

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

mitochondrial cyt ''c'' and prokaryotic 'short' cyt ''c''₂ exemplified by '' Rhodopila globiformis'' cyt ''c''₂; class IA includes 'long' cyt ''c''₂, such as '' Rhodospirillum rubrum'' cyt ''c''₂ and '' Aquaspirillum itersonii'' cyt ''c''₅₅₀, which have several extra loops by comparison with class IB cyt ''c''. The linked InterPro entry represents mono-haem cytochrome c proteins (excluding class II and f-type cytochromes), such as cytochromes ''c, c1, c2, c5, c555, c550-c553, c556, c6'' and ''cbb3''. Diheme cytochrome c () are proteins with a class I cluster and a unique cluster.

Subclasses

*Cytochrome c, class IA/IB *Cytochrome c, class IC *Cytochrome c, class ID *Cytochrome c, class IE

Class II

The heme group in class II cytochrome ''c'' proteins is attached to a C-terminal binding motif. The structural fold of class II ''c''-type cytochromes contains a four

α-helix An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...

bundle with the covalently attached heme group at its core. Representatives of class II are the high-spin cytochrome ''c''' and a number of low-spin cytochromes ''c'', e.g. cyt ''c''₅₅₆. The cyt ''c''' are capable of binding such

ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...

as CO, NO or CN⁻, albeit with rate and equilibrium constants 100 to 1,000,000-fold smaller than other high-spin hemeproteins. This, coupled with its relatively low

redox Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is t ...

potential, makes it unlikely that cyt ''c''' is a terminal oxidase. Thus cyt ''c''' probably functions as an electron transfer protein. The 3D structures of a number of cyt ''c''' have been determined which show that the proteins usually exist as a dimer. The ''Chromatium vinosum'' cyt ''c''' exhibits dimer dissociation upon ligand binding.

Class III

Proteins containing multiple covalently attached heme groups with low redox potential are included in class III. The heme C groups, all bis-histidinyl coordinated, are structurally and functionally nonequivalent and present different

potentials in the range 0 to −400 mV. Members of this class are e.g. cytochrome ''c''₇ (triheme), cytochrome ''c''₃ (tetraheme), and high-molecular-weight cytochrome ''c'' (Hmc), containing 16 heme groups with only 30-40 residues per heme group. The 3D

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

s of a number of cyt ''c''₃

s have been determined. The proteins consist of four or five α-helices and two β-sheets wrapped around a compact core of four non-parallel hemes, which present a relatively high degree of exposure to the

solvent A solvent (from the Latin language, Latin ''wikt:solvo#Latin, solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a Solution (chemistry), solution. A solvent is usually a liquid but can also be a solid, a gas ...

. The overall protein architecture, heme plane orientations and iron-iron distances are highly conserved. An example is the photosynthetic reaction centre of '' Rhodopseudomonas viridis'' that contains a tetraheme cytochrome ''c'' subunit.

Class IV

According to Ambler (1991), Cytochrome ''c'' proteins containing other prosthetic groups besides heme C, such as flavocytochromes ''c'' (sulfide dehydrogenase) and cytochromes ''cd₁'' (nitrite reductase) belong to class IV. As this grouping is more related to ''how'' the heme group is used instead of ''what'' the domains themselves look like, proteins placed in this group tend to be scattered in others in bioinformatic groupings.

Biogenesis

The attachment of the heme group is physically separated from the

protein biosynthesis Protein biosynthesis, or protein synthesis, is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the produc ...

. Proteins are synthesized within the

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

and

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

, while the maturation of cytochromes ''c'' occurs in the periplasm of

prokaryotes A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Greek (), meaning 'before', and (), meaning 'nut' ...

, the

intermembrane space The intermembrane space (IMS) is the space occurring between or involving two or more membranes. In cell biology, it is most commonly described as the region between the Inner mitochondrial membrane, inner membrane and the Outer mitochondrial memb ...

of mitochondria or the stroma of

chloroplast A chloroplast () is a type of membrane-bound organelle, organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. Chloroplasts have a high concentration of chlorophyll pigments which captur ...

s. Several biochemical pathways have been discovered that differ depending on organism.

System I

Also called cytochrome ''c'' maturation (ccm) and found in

Pseudomonadota Pseudomonadota (synonym "Proteobacteria") is a major phylum of gram-negative bacteria. Currently, they are considered the predominant phylum within the domain of bacteria. They are naturally found as pathogenic and free-living (non- parasitic) ...

, plant mitochondria, some

protozoa Protozoa (: protozoan or protozoon; alternative plural: protozoans) are a polyphyletic group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic debris. Historically ...

l mitochondria, deinococci, and

archaea Archaea ( ) is a Domain (biology), domain of organisms. Traditionally, Archaea only included its Prokaryote, prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even thou ...

. Ccm comprises at least eight membrane proteins (CcmABCDEFGH) that are needed for electron transfer to the heme group, apo-cytochrome handling and attachment of the heme to the apo-cytochrome. An ABC-transporter-like complex formed by CcmA₂BCD attaches a heme group to CcmE with the use of ATP. CcmE transports the heme to CcmF where the attachment to the apo-cytochrome occurs. Transport of the apoprotein from the cytoplasm to the periplasm happens via the Sec translocation system. CcmH is used by the system to recognize the apo-cytochrome and direct it to CcmF.

System II

Cytochromes ''c'' in

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain is ...

bacteria,

cyanobacteria Cyanobacteria ( ) are a group of autotrophic gram-negative bacteria that can obtain biological energy via oxygenic photosynthesis. The name "cyanobacteria" () refers to their bluish green (cyan) color, which forms the basis of cyanobacteri ...

, and some Pseudomonadota are produced by the cytochrome ''c'' synthesis (ccs) system. It is composed of two membrane proteins CcsB and CcsA. The CcsBA protein complex was suggested to act as a heme transporter during the attachment process. In some organisms such as '' Helicobacter hepaticus'' both proteins are found as a fused single protein. Apoprotein transport occurs via the Sec translocon as well.

System III

Fungal A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as one of the tradit ...

vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...

and

invertebrate Invertebrates are animals that neither develop nor retain a vertebral column (commonly known as a ''spine'' or ''backbone''), which evolved from the notochord. It is a paraphyletic grouping including all animals excluding the chordata, chordate s ...

mitochondria produce cytochrome ''c'' proteins with a single enzyme called HCCS ( holocytochrome c synthase) or cytochrome ''c'' heme lyase (CCHL). The protein is attached to the inner membrane of the intermembrane space. In some organisms, such as ''

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...

'', cytochrome ''c'' and cytochrome ''c''₁ are synthesized by separate heme lyases, CCHL and CC1HL respectively. In ''

Homo sapiens Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

'' a single HCCS is used for the biosynthesis of both cytochrome ''c'' proteins.

System IV

Four membrane proteins are necessary for the attachment of a heme in cytochrome ''b''6. A major difference to systems I-III is that the heme attachment occurs at the opposite side of the lipid bilayer compared to the other systems.

Human proteins containing this domain

CYCS; CYC1

References

{{InterPro content, IPR020942 Protein domains Peripheral membrane proteins