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

cytochromes Cytochromes are redox-active proteins containing a heme, with a central Fe atom at its core, as a cofactor. They are involved in electron transport chain and redox catalysis. They are classified according to the type of heme and its mode of bi ...

, or

heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consisti ...

-containing

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s, that have heme C

covalently A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

attached to the peptide backbone via one or two

thioether In organic chemistry, an organic 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 sulfides have foul odors. A sul ...

bonds. These bonds are in most cases part of a specific Cys-X-X-Cys-

His His or HIS may refer to: Computing * Hightech Information System, a Hong Kong graphics card company * Honeywell Information Systems * Hybrid intelligent system * Microsoft Host Integration Server Education * Hangzhou International School, in ...

(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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

. 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 m ...

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

iron Iron () is a chemical element with symbol Fe (from la, ferrum) 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, right in f ...

. 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 (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as a ...

. Cytochromes ''c'' possess a wide range of properties and function as

electron transfer Electron transfer (ET) occurs when an electron relocates from an atom or molecule to another such chemical entity. ET is a mechanistic description of certain kinds of redox reactions involving transfer of electrons. Electrochemical processes ar ...

proteins or

catalyse Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

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 held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

of 8-12

kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...

and a single heme group belong to class I. It includes the

low-spin Spin states when describing transition metal coordination complexes refers to the potential spin configurations of the central metal's d electrons. For several oxidation states, metals can adopt high-spin and low-spin configurations. The ambiguity o ...

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 ami ...

, 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 amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...

residue about 40 residues further on towards the C-terminus. The typical class I fold contains five

α-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

. On the basis of sequence similarity, class I cytC were further subdivided into five classes, IA to IE. Class IB includes the

eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

mitochondrial cyt ''c'' and

prokaryotic A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...

'short' cyt ''c''₂ exemplified by ''

Rhodopila globiformis ''Rhodopila globiformis'' is a species of bacteria, formerly known as ''Rhodopseudomonas globiformis''. It is a motile, spherical organism. Cells can grow between 1.6 and 1.8 μm in diameter. The photopigments consist of bacteriochlorophyll aP ...

'' cyt ''c''₂; class IA includes 'long' cyt ''c''₂, such as ''

Rhodospirillum rubrum ''Rhodospirillum rubrum'' (''R. rubrum'') is a Gram-negative, pink-coloured bacterium, with a size of 800 to 1000 nanometers. It is a facultative anaerobe, thus capable of using oxygen for aerobic respiration under aerobic conditions, or an alte ...

'' cyt ''c''₂ and ''

Aquaspirillum itersonii ''Aquaspirillum'' (ak'wă-spī-ril'ŭm) is a genus of helical aerobic bacteria in the family ''Neisseriaceae'' that lives in freshwater. Taxonomy In 1832, the genus ''Spirillum'' was created and encompassed an array of helical bacteria. In 1 ...

'' 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''. Dihaem 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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

binding motif. The structural fold of class II ''c''-type cytochromes contains a four

α-helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...

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 (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 electro ...

as CO, NO or CN⁻, albeit with rate and equilibrium constants 100 to 1,000,000-fold smaller than other high-spin

hemeprotein A hemeprotein (or haemprotein; also hemoprotein or haemoprotein), or heme protein, is a protein that contains a heme prosthetic group. They are a very large class of metalloproteins. The heme group confers functionality, which can include oxygen ...

s. This, coupled with its relatively low

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

potential, makes it unlikely that cyt ''c''' is a terminal

oxidase In biochemistry, an oxidase is an enzyme that catalyzes oxidation-reduction reactions, especially one involving dioxygen (O2) as the electron acceptor. In reactions involving donation of a hydrogen atom, oxygen is reduced to water (H2O) or hydro ...

. Thus cyt ''c''' probably functions as an

electron transfer protein The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family, and are generally thought to be elementary particles because they have no k ...

. The 3D structures of a number of cyt ''c''' have been determined which show that the proteins usually exist as a

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ...

. The ''Chromatium vinosum'' cyt ''c''' exhibits

dissociation Dissociation, in the wide sense of the word, is an act of disuniting or separating a complex object into parts. Dissociation may also refer to: * Dissociation (chemistry), general process in which molecules or ionic compounds (complexes, or salts) ...

upon

ligand binding In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mo ...

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 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 ...

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 4-5

and 2

β-sheets The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

wrapped around a compact core of four non-parallel hemes, which present a relatively high degree of exposure to the

solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...

. The overall protein architecture, heme plane orientations and iron-iron distances are highly conserved. An example is the

Photosynthetic reaction centre A photosynthetic reaction center is a complex of several proteins, pigments and other co-factors that together execute the primary energy conversion reactions of photosynthesis. Molecular excitations, either originating directly from sunlight or t ...

of ''

Rhodopseudomonas ''Rhodopseudomonas'' is a genus of bacteria from the family Nitrobacteraceae. Phylogeny The currently accepted taxonomy is based on the List of Prokaryotic names with Standing in Nomenclature List of Prokaryotic names with Standing in Nomenc ...

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 cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...

. Proteins are synthesized within the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

and

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

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

periplasm The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the ''periplasmic space'' in gram-negative bacteria. Using cryo-electron microscopy it has been found that ...

of prokaryots, the intermembrane space of mitochondria or the stroma of

chloroplast A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in ...

s. Several

biochemical pathways In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...

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. The renaming of phyla in 2021 remains controversial among microbiologists, many of whom continue to use the earlier names of long standing in the literature. The ...

, plant mitochondria, some

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

l mitochondria,

deinococci ''Deinococcota'' (synonym, ''Deinococcus-Thermus'') is a phylum of bacteria with a single class, ''Deinococci'', that are highly resistant to environmental hazards, also known as extremophiles. These bacteria have thick cell walls that give them ...

, and

archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...

. Ccm comprises at least eight

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

s (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 The ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transpo ...

-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. Gram-positive bacte ...

bacteria,

cyanobacteria Cyanobacteria (), also known as Cyanophyta, are a phylum of gram-negative bacteria that obtain energy via photosynthesis. The name ''cyanobacteria'' refers to their color (), which similarly forms the basis of cyanobacteria's common name, blu ...

, 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 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 a kingdom, separately from th ...

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

and

invertebrate Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...

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 fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...

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

Homo sapiens Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

'' 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 Cytochrome c1, heme protein, mitochondrial (CYC1), also known as UQCR4, MC3DN6, Complex III subunit 4, Cytochrome b-c1 complex subunit 4, or Ubiquinol-cytochrome-c reductase complex cytochrome c1 subunit is a protein that in humans is encoded by t ...

References

{{InterPro content, IPR020942 Protein domains Peripheral membrane proteins