cytochrome c

Cytochrome c is a highly conserved protein across the spectrum of eukaryotic species, found in plants, animals, fungi, and many unicellular organisms. This, along with its small size (molecular weight about 12,000 daltons),{{Cite web |title=Cytochrome c – Homo sapiens (Human) |url=https://www.uniprot.org/uniprot/P99999#section_seq |website=P99999 |publisher=UniProt Consortium |quote=mass is 11,749 Daltons}} makes it useful in studies of cladistics.{{Cite journal |vauthors=Margoliash E |date=October 1963 |title=Primary structure and evolution of cytochrome c |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=50 |issue=4 |pages=672–9 |bibcode=1963PNAS...50..672M |doi=10.1073/pnas.50.4.672 |pmc=221244 |pmid=14077496 |doi-access=free}} Cytochrome c has been studied for the glimpse it gives into evolutionary biology.

Cytochrome c has a primary structure consisting of a chain of about 100 amino acids. Many higher-order organisms possess a chain of 104 amino acids.{{Cite web |title=Amino acid sequences in cytochrome c proteins from different species |url=http://www.indiana.edu/~ensiweb/lessons/molb.ws.pdf |archive-url=https://web.archive.org/web/20131228191245/http://www.indiana.edu/~ensiweb/lessons/molb.ws.pdf |archive-date=2013-12-28}}, adapted from {{cite book | vauthors = Strahler AN |title=Science and earth history: the evolution/creation controversy |date=1999 |publisher=Prometheus Books |location=Amherst, N.Y |isbn=978-1-57392-717-8 | page = 348 }} The sequence of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs from that of horses.{{Cite book |url=https://books.google.com/books?id=zdeWdF_NQhEC&q=chimpanzee+rhesus+cytochrome+c&pg=PA79 |title=Genes, culture, and human evolution: a synthesis |vauthors=Lurquin PF, Stone L, Cavalli-Sforza LL |publisher=Blackwell |year=2007 |isbn=978-1-4051-5089-7 |location=Oxford |page=79}}

Cytochrome c has an amino acid sequence that is highly conserved in eukaryotes, varying by only a few residues. In more than thirty species tested in one study, 34 of the 104 amino acids were conserved (identical at their characteristic position).{{Cite book |url=https://archive.org/details/biochemistry00stry_1/page/362 |title=Biochemistry |vauthors=Stryer L |date=1975 |publisher=W.H. Freeman and Company |isbn=978-0-7167-0174-3 |edition=1st |location=San Francisco |page=[https://archive.org/details/biochemistry00stry_1/page/362 362] |url-access=registration}} For example, human cytochrome oxidase reacted with wheat cytochrome c, in vitro; which held true for all pairs of species tested. In addition, the redox potential of +0.25 volts is the same in all cytochrome c molecules studied.

File:Tunafish cytochrome c crystals grown in microgravity.jpg

Cytochrome c belongs to class I of the c-type cytochrome family{{Cite journal |vauthors=Ambler RP |date=May 1991 |title=Sequence variability in bacterial cytochromes c |journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics |volume=1058 |issue=1 |pages=42–7 |doi=10.1016/S0005-2728(05)80266-X |pmid=1646017}} and contains a characteristic CXXCH (cysteine-any-any-cysteine-histidine) amino acid motif that binds heme.{{Cite journal |vauthors=Mavridou DA, Ferguson SJ, Stevens JM |date=March 2013 |title=Cytochrome c assembly |journal=IUBMB Life |volume=65 |issue=3 |pages=209–16 |doi=10.1002/iub.1123 |pmid=23341334 |s2cid=32216217}} This motif is located towards the N-terminus of the peptide chain and contains a histidine as the 5th ligand of the heme iron. The 6th ligand is provided by a methionine residue found towards the C-terminus. The protein backbone is folded into five α-helices that are numbered α1-α5 from N-terminus to C-terminus. Helices α3, α4 and α5 are referred to as 50s, 60s and 70s helices, respectively, when referring to mitochondrial cytochrome c.{{Cite journal |vauthors=Liu J, Chakraborty S, Hosseinzadeh P, Yu Y, Tian S, Petrik I, Bhagi A, Lu Y |date=2014-04-23 |title=Metalloproteins Containing Cytochrome, Iron–Sulfur, or Copper Redox Centers |journal=Chemical Reviews |language=EN |volume=114 |issue=8 |pages=4366–4469 |doi=10.1021/cr400479b |issn=0009-2665 |pmc=4002152 |pmid=24758379}}

File:Heme c.svg

While most heme proteins are attached to the prosthetic group through iron ion ligation and tertiary interactions, the heme group of cytochrome c makes thioether bonds with two cysteine side chains of the protein.{{Cite journal |vauthors=Kang X, Carey J |date=November 1999 |title=Role of heme in structural organization of cytochrome c probed by semisynthesis |journal=Biochemistry |volume=38 |issue=48 |pages=15944–51 |doi=10.1021/bi9919089 |pmid=10625461}} One of the main properties of heme c, which allows cytochrome c to have variety of functions, is its ability to have different reduction potentials in nature. This property determines the kinetics and thermodynamics of an electron transfer reaction.{{Cite journal |vauthors=Zhao Y, Wang ZB, Xu JX |date=January 2003 |title=Effect of cytochrome c on the generation and elimination of O{{sub|2}}{{sup|–}} and H{{sub|2}}O{{sub|2}} in mitochondria |journal=The Journal of Biological Chemistry |volume=278 |issue=4 |pages=2356–60 |doi=10.1074/jbc.M209681200 |pmid=12435729 |doi-access=free}}

The dipole moment has an important role in orienting proteins to the proper directions and enhancing their abilities to bind to other molecules.{{Cite journal |vauthors=Koppenol WH, Margoliash E |date=April 1982 |title=The asymmetric distribution of charges on the surface of horse cytochrome c. Functional implications |journal=The Journal of Biological Chemistry |volume=257 |issue=8 |pages=4426–37 |doi=10.1016/S0021-9258(18)34740-9 |pmid=6279635 |doi-access=free}}{{Cite journal |vauthors=Koppenol WH, Rush JD, Mills JD, Margoliash E |date=July 1991 |title=The dipole moment of cytochrome c |journal=Molecular Biology and Evolution |volume=8 |issue=4 |pages=545–58 |doi=10.1093/oxfordjournals.molbev.a040659 |pmid=1656165 |doi-access=free}} The dipole moment of cytochrome c results from a cluster of negatively charged amino acid side chains at the "back" of the enzyme. Despite variations in the number of bound heme groups and variations in sequence, the dipole moment of vertebrate cytochromes c is remarkably conserved. For example, vertebrate cytochromes c all have a dipole moment of approximately 320 debye while cytochromes c of plants and insects have a dipole moment of approximately 340 debye.

{{main|Electron transport chain}}

Cytochrome c is an essential component of the respiratory electron transport chain in mitochondria. The heme group of cytochrome c accepts electrons from the Complex III and transports them to Complex IV, while it transfers energy in the opposite direction.{{cn|date=November 2024}}

Cytochrome c can also catalyze several redox reactions such as hydroxylation and aromatic oxidation, and shows peroxidase activity by oxidation of various electron donors such as 2,2-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), 2-keto-4-thiomethyl butyric acid and 4-aminoantipyrine.{{cn|date=November 2024}}

A bacterial cytochrome c functions as a nitrite reductase.{{Cite book |title=The Metal-Driven Biogeochemistry of Gaseous Compounds in the Environment |vauthors=Schneider J, Kroneck PM |publisher=Springer |year=2014 |isbn=978-94-017-9268-4 |veditors=Kroneck PM, Torres ME |series=Metal Ions in Life Sciences |volume=14 |pages=211–236 |chapter=The Production of Ammonia by Multiheme Cytochromes C |doi=10.1007/978-94-017-9269-1_9 |pmid=25416396}}

Cytochrome c was also discovered in 1996 by Xiaodong Wang to have an intermediate role in apoptosis, a controlled form of cell death used to kill cells in the process of development or in response to infection or DNA damage.{{Cite journal |vauthors=Liu X, Kim CN, Yang J, Jemmerson R, Wang X |date=July 1996 |title=Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c |journal=Cell |volume=86 |issue=1 |pages=147–57 |doi=10.1016/S0092-8674(00)80085-9 |pmid=8689682 |s2cid=12604356 |doi-access=free}}

Cytochrome c binds to cardiolipin in the inner mitochondrial membrane, thus anchoring its presence and keeping it from releasing out of the mitochondria and initiating apoptosis. While the initial attraction between cardiolipin and cytochrome c is electrostatic due to the extreme positive charge on cytochrome c, the final interaction is hydrophobic, where a hydrophobic tail from cardiolipin inserts itself into the hydrophobic portion of cytochrome c.{{cn|date=November 2024}}

During the early phase of apoptosis, mitochondrial ROS production is stimulated, and cardiolipin is oxidized by a peroxidase function of the cardiolipin–cytochrome c complex. The hemoprotein is then detached from the mitochondrial inner membrane and can be extruded into the soluble cytoplasm through pores in the outer membrane.{{Cite journal |vauthors=Orrenius S, Zhivotovsky B |date=September 2005 |title=Cardiolipin oxidation sets cytochrome c free |journal=Nature Chemical Biology |volume=1 |issue=4 |pages=188–9 |doi=10.1038/nchembio0905-188 |pmid=16408030 |s2cid=45381495}}

The sustained elevation in calcium levels precedes cyt c release from the mitochondria. The release of small amounts of cyt c leads to an interaction with the IP3 receptor (IP3R) on the endoplasmic reticulum (ER), causing ER calcium release. The overall increase in calcium triggers a massive release of cyt c, which then acts in the positive feedback loop to maintain ER calcium release through the IP3Rs.{{Cite journal |vauthors=Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH |date=December 2003 |title=Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis |journal=Nature Cell Biology |volume=5 |issue=12 |pages=1051–61 |doi=10.1038/ncb1063 |pmid=14608362 |s2cid=27761335}} This explains how the ER calcium release can reach cytotoxic levels. This release of cytochrome c in turn activates caspase 9, a cysteine protease. Caspase 9 can then go on to activate caspase 3 and caspase 7, which destroy the cell from within.{{cn|date=November 2024}}

One of the ways cell apoptosis is activated is by release of cytochrome c from the mitochondria into cytosol. A study has shown that cells are able to protect themselves from apoptosis by blocking the release of cytochrome c using Bcl-x_L.{{Cite journal |vauthors=Kharbanda S, Pandey P, Schofield L, Israels S, Roncinske R, Yoshida K, Bharti A, Yuan ZM, Saxena S, Weichselbaum R, Nalin C, Kufe D |date=June 1997 |title=Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=94 |issue=13 |pages=6939–42 |bibcode=1997PNAS...94.6939K |doi=10.1073/pnas.94.13.6939 |pmc=21263 |pmid=9192670 |doi-access=free}} Another way that cells can control apoptosis is by phosphorylation of Tyr48, which turns cytochrome c into an anti-apoptotic switch.{{Cite journal |vauthors=García-Heredia JM, Díaz-Quintana A, Salzano M, Orzáez M, Pérez-Payá E, Teixeira M, De la Rosa MA, Díaz-Moreno I |date=December 2011 |title=Tyrosine phosphorylation turns alkaline transition into a biologically relevant process and makes human cytochrome c behave as an anti-apoptotic switch |journal=Journal of Biological Inorganic Chemistry |volume=16 |issue=8 |pages=1155–68 |doi=10.1007/s00775-011-0804-9 |pmid=21706253 |s2cid=24156094}}

File:Removal of O2- and H2O2 by cytochrome c.png

In addition to its well-known roles in the electron transport chain and cell apoptosis, according to a 2008 study cytochrome c can also act as an antioxidative enzyme in the mitochondria; it does so by removing superoxide ({{chem2|O2-}}) and hydrogen peroxide (H{{sub|2}}O{{sub|2}}) from mitochondria.{{Cite journal |vauthors=Bowman SE, Bren KL |date=December 2008 |title=The chemistry and biochemistry of heme c: functional bases for covalent attachment |journal=Natural Product Reports |volume=25 |issue=6 |pages=1118–30 |doi=10.1039/b717196j |pmc=2654777 |pmid=19030605}} Therefore, not only is cytochrome c required in the mitochondria for cellular respiration, but it is also needed in the mitochondria to limit the production of {{chem2|O2-}} and {{chem2|H2O2}}.

Cytochrome c is widely believed to be localised solely in the mitochondrial intermembrane space under normal physiological conditions.{{Cite journal |vauthors=Neupert W |year=1997 |title=Protein import into mitochondria |journal=Annual Review of Biochemistry |volume=66 |pages=863–917 |doi=10.1146/annurev.biochem.66.1.863 |pmid=9242927}} The release of cytochrome c from mitochondria to the cytosol, where it activates the caspase family of proteases, is believed to be the primary trigger leading to the onset of apoptosis.{{Cite journal |vauthors=Kroemer G, Dallaporta B, Resche-Rigon M |year=1998 |title=The mitochondrial death/life regulator in apoptosis and necrosis |journal=Annual Review of Physiology |volume=60 |pages=619–42 |doi=10.1146/annurev.physiol.60.1.619 |pmid=9558479}} Measuring the amount of cytochrome c leaking from mitochondria to cytosol, and out of the cell to culture medium, is a sensitive method to monitor the degree of apoptosis.{{Cite journal |vauthors=Loo JF, Lau PM, Ho HP, Kong SK |date=October 2013 |title=An aptamer-based bio-barcode assay with isothermal recombinase polymerase amplification for cytochrome-c detection and anti-cancer drug screening |journal=Talanta |volume=115 |pages=159–65 |doi=10.1016/j.talanta.2013.04.051 |pmid=24054573}}{{Cite journal |vauthors=Waterhouse NJ, Trapani JA |date=July 2003 |title=A new quantitative assay for cytochrome c release in apoptotic cells |journal=Cell Death and Differentiation |volume=10 |issue=7 |pages=853–5 |doi=10.1038/sj.cdd.4401263 |pmid=12815469 |doi-access=free}} However, detailed immuno-electronmicroscopic studies with rat tissues sections employing cytochrome c specific antibodies provide compelling evidence that cytochrome c under normal cellular conditions is also present at extramitochondrial locations.{{Cite journal |vauthors=Soltys BJ, Andrews DW, Jemmerson R, Gupta RS |year=2001 |title=Cytochrome-C localises in secretory granules in pancreas and anterior pituitary |journal=Cell Biology International |volume=25 |issue=4 |pages=331–8 |doi=10.1006/cbir.2000.0651 |pmid=11319839 |s2cid=2106599}} In pancreatic acinar cells and the anterior pituitary, strong and specific presence of cytochrome c was detected in zymogen granules and in growth hormone granules, respectively. In the pancreas, cytochrome c was also found in condensing vacuoles and in the acinar lumen. The extramitochondrial localisation of cytochrome c was shown to be specific as it was completely abolished upon adsorption of the primary antibody with purified cytochrome c. Besides cytochrome c, extramitochondrial localisation has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.{{Cite book |title=The Biology of Extracellular Molecular Chaperones |vauthors=Gupta RS, Ramachandra NB, Bowes T, Singh B |year=2008 |isbn=978-0-470-75403-0 |veditors=Chadwick D, Goode J |series=Novartis Foundation Symposia |volume=291 |pages=59–68; discussion 69–73, 137–40 |chapter=Unusual Cellular Disposition of the Mitochondrial Molecular Chaperones Hsp60, Hsp70 and Hsp10 |doi=10.1002/9780470754030.ch5 |pmid=18575266}}{{Cite journal |vauthors=Sadacharan SK, Singh B, Bowes T, Gupta RS |date=November 2005 |title=Localisation of mitochondrial DNA encoded cytochrome c oxidase subunits I and II in rat pancreatic zymogen granules and pituitary growth hormone granules |journal=Histochemistry and Cell Biology |volume=124 |issue=5 |pages=409–21 |doi=10.1007/s00418-005-0056-2 |pmid=16133117 |s2cid=24440427}}{{Cite book |title=Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective |vauthors=Soltys BJ, Gupta RS |year=2000 |isbn=978-0-12-364598-2 |series=International Review of Cytology |volume=194 |pages=133–96 |doi=10.1016/s0074-7696(08)62396-7 |pmid=10494626}} This raises the possibility of the existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.{{Cite journal |vauthors=Soltys BJ, Gupta RS |date=May 1999 |title=Mitochondrial-matrix proteins at unexpected locations: are they exported? |journal=Trends in Biochemical Sciences |volume=24 |issue=5 |pages=174–7 |doi=10.1016/s0968-0004(99)01390-0 |pmid=10322429}}

File:Peroxynitrous-acid-2D.svg]]

Cytochrome c has been used to detect peroxide production in biological systems. As superoxide is produced, the number of oxidised cytochrome c³⁺ increases, and reduced cytochrome c²⁺ decreases.{{Cite journal |vauthors=McCord JM, Fridovich I |date=November 1969 |title=Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein) |journal=The Journal of Biological Chemistry |volume=244 |issue=22 |pages=6049–55 |doi=10.1016/S0021-9258(18)63504-5 |pmid=5389100 |doi-access=free}} However, superoxide is often produced with nitric oxide. In the presence of nitric oxide, the reduction of cytochrome c³⁺ is inhibited.{{Cite journal |vauthors=Thomson L, Trujillo M, Telleri R, Radi R |date=June 1995 |title=Kinetics of cytochrome c²⁺ oxidation by peroxynitrite: implications for superoxide measurements in nitric oxide-producing biological systems |journal=Archives of Biochemistry and Biophysics |volume=319 |issue=2 |pages=491–7 |doi=10.1006/abbi.1995.1321 |pmid=7786032}} This leads to the oxidisation of cytochrome c{{sup|2+}} to cytochrome c{{sup|3+}} by peroxynitrous acid, an intermediate made through the reaction of nitric oxide and superoxide. Presence of peroxynitrite or H{{sub|2}}O{{sub|2}} and nitrogen dioxide NO{{sub|2}} in the mitochondria can be lethal since they nitrate tyrosine residues of cytochrome c, which leads to disruption of cytochrome c's function as an electron carrier in the electron transport chain.{{Cite journal |vauthors=Domazou AS, Gebicka L, Didik J, Gebicki JL, van der Meijden B, Koppenol WH |date=April 2014 |title=The kinetics of the reaction of nitrogen dioxide with iron(II)- and iron(III) cytochrome c |journal=Free Radical Biology & Medicine |volume=69 |pages=172–80 |doi=10.1016/j.freeradbiomed.2014.01.014 |pmid=24447894}}

Cytochrome C has also been widely studied as an enzyme with peroxidase-like activity. Cytochrome C was conjugated to charged polymer to test its peroxidase-like activity.{{Cite journal |vauthors=Zhang Y, Wang Q, Hess H |date=March 2017 |title=Increasing enzyme cascade throughput by pH-engineering the microenvironment of individual enzymes. |journal=ACS Catalysis |volume=7 |issue=3 |pages=2047-2051 |doi=10.1021/acscatal.7b01766}}{{Cite journal |vauthors=Benson KR, Gorecki J, Nikiforov A, Tsui W, Kasi RM, Kumar CV |date=April 2019 |title=Cytochrome c-poly(acrylic acid) conjugates with improved peroxidase turnover number |journal=Organic & Biomolecular Chemistry |volume=17 |issue=16 |pages=4043–4048 |doi=10.1039/c9ob00541b |pmid=30950479}} Inspired from natural examples of enzyme encapsulation in protein-based cage structures (Example: Carboxysomes, Ferritin, and Encapsulin), Cytochrome C was encapsulated in a 9 nm small self-assembling DNA binding protein from nutrient starved cells (Dps) protein cage using chimeric self-assembly approach. Authors observed unique catalytic activity behavior upon encapsulating enzyme inside a protein-cage, which was different from enzyme in solution. This was attributed to local microenvironment provided by Dps nanocage's interior cavity which is different than bulk.{{Cite journal |vauthors=Waghwani HK, Douglas, T |date=March 2021 |title=Cytochrome C with peroxidase-like activity encapsulated inside the small DPS protein nanocage |journal=Journal of Materials Chemistry B |volume=9 |issue=14 |pages=3168–3179 |doi=10.1039/d1tb00234a |pmid=33885621 |doi-access=free}}

• Cytochrome c oxidase
• Methanol dehydrogenase (cytochrome c)

{{Reflist|33em}}

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{{refend}}

{{Commons category|Cytochrome c}}

• [https://www.youtube.com/watch?v=l4D0YxGi5Ec Apoptosis & Caspase 3] – PMAP The Proteolysis Map-animation
• {{MeshName|Cytochrome+c}}
• {{PDBe-KB2|P99999|Cytochrome c}}

{{PDB Gallery|geneid=54205}}

{{Electron transport chain}}

{{Fas apoptosis signaling pathway}}

Category:Cellular respiration

Category:Cytochromes

Category:Programmed cell death

Category:Peripheral membrane proteins

Category:Moonlighting proteins