View source for Cytochrome c

{{short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox gene}}
[[File:Cytochrome c image 2.png|thumb|Heme prosthetic group of cytochrome c, consisting of a rigid porphyrin ring coordinated with an iron atom.]]
The '''cytochrome complex''', or '''cyt c''', is a small [[hemeprotein]] found loosely associated with the [[inner mitochondrial membrane|inner membrane]] of the [[mitochondrion]], where it plays a critical role in [[cellular respiration]]. 
It [[Electron transport chain|transfers electrons]] between [[Coenzyme Q - cytochrome c reductase|Complexes III]] (Coenzyme Q – Cyt c reductase) and [[cytochrome c oxidase|IV]] (Cyt c oxidase). Cytochrome c is highly [[Water soluble|water-soluble]], unlike other [[cytochrome]]s. It is capable of undergoing [[oxidation]] and [[redox|reduction]] as its [[iron]] atom converts between the [[ferrous]] and [[ferric]] forms, but does not bind [[oxygen]].  It also plays a major role in cell [[apoptosis]]. In humans, cytochrome c is encoded by the ''CYCS'' [[gene]].<ref name="entrez">{{Cite web |title=Entrez Gene: cytochrome c |url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=54205}}</ref><ref name="pmid11790791">{{Cite journal |vauthors=Tafani M, Karpinich NO, Hurster KA, Pastorino JG, Schneider T, Russo MA, Farber JL |date=March 2002 |title=Cytochrome c release upon Fas receptor activation depends on translocation of full-length bid and the induction of the mitochondrial permeability transition |journal=[[The Journal of Biological Chemistry]] |volume=277 |issue=12 |pages=10073–82 |doi=10.1074/jbc.M111350200 |pmid=11790791 |doi-access=free}}</ref>

== Species distribution ==

Cytochrome c is a highly [[conserved sequence|conserved]] protein across the spectrum of [[eukaryote|eukaryotic]] species, found in plants, animals, fungi, and many unicellular organisms. This, along with its small size (molecular weight about 12,000 [[dalton (unit)|dalton]]s),<ref name="urlCytochrome c - Homo sapiens (Human)">{{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}}</ref> makes it useful in studies of [[cladistics]].<ref name="pmid14077496">{{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}}</ref> 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 acid]]s. Many higher-order organisms possess a chain of 104 amino acids.<ref name="indiana">{{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 }}</ref> The sequence of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs from that of horses.<ref name="isbn978-1-4051-5089-7">{{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}}</ref>

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).<ref name="stryer">{{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}}</ref>  For example, human [[cytochrome oxidase]] reacted with wheat cytochrome ''c'', ''in vitro''; which held true for all pairs of species tested.<ref name="stryer" /> In addition, the redox potential of +0.25 volts is the same in all cytochrome ''c'' molecules studied.<ref name="stryer" />

== Structure ==

[[File:Tunafish cytochrome c crystals grown in microgravity.jpg|left|thumb|Tunafish cytochrome c crystals (~5 mm long) grown by liquid–liquid diffusion under microgravity conditions in outer space.<ref>{{Cite journal |vauthors=McPherson A, DeLucas LJ |year=2015 |title=Microgravity protein crystallization |journal=npj Microgravity |volume=1 |pages=15010 |doi=10.1038/npjmgrav.2015.10 |pmc=5515504 |pmid=28725714}}</ref>]]

Cytochrome c belongs to class I of the [[Cytochrome c family|c-type cytochrome family]]<ref name="pmid1646017">{{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}}</ref> and contains a characteristic CXXCH (cysteine-any-any-cysteine-histidine) amino acid motif that binds heme.<ref name="pmid23341334">{{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}}</ref> 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 [[Alpha helix|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.<ref>{{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}}</ref>

=== Heme c ===

[[File:Heme c.svg|thumb|Structure of heme c]]

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.<ref>{{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 (journal)|Biochemistry]] |volume=38 |issue=48 |pages=15944–51 |doi=10.1021/bi9919089 |pmid=10625461}}</ref> 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.<ref>{{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}}</ref>

=== Dipole moment ===

The dipole moment has an important role in orienting proteins to the proper directions and enhancing their abilities to bind to other molecules.<ref>{{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}}</ref><ref name="Koppenol_1982">{{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}}</ref> The dipole moment of cytochrome c results from a cluster of negatively charged amino acid side chains at the "back" of the enzyme.<ref name="Koppenol_1982" /> 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.<ref name="Koppenol_1982" />

== Function ==

=== Electron transport chain ===
{{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|bc{{sub|1}} Complex III]] and transports them to [[cytochrome c oxidase|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 [[cytochrome c nitrite reductase|nitrite reductase]].<ref>{{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}}</ref>

=== Role in apoptosis ===

Cytochrome c was also discovered in 1996 by [[Xiaodong Wang (biochemist)|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.<ref name="pmid8689682">{{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 (journal)|Cell]] |volume=86 |issue=1 |pages=147–57 |doi=10.1016/S0092-8674(00)80085-9 |pmid=8689682 |s2cid=12604356 |doi-access=free}}</ref>

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.<ref name="PMID16408030">{{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}}</ref>

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 [[Inositol triphosphate receptor|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.<ref name="pmid14608362">{{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}}</ref> 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}}

=== Inhibition of apoptosis ===

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<sub>L</sub>.<ref>{{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}}</ref> Another way that cells can control apoptosis is by phosphorylation of Tyr48, which turns cytochrome c into an anti-apoptotic switch.<ref>{{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}}</ref>

=== As an antioxidative enzyme ===

[[File:Removal of O2- and H2O2 by cytochrome c.png|thumb|Removal of {{chem2|O2-}} and H{{sub|2}}O{{sub|2}} by cytochrome c]]

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]].<ref name="Bowman_2008">{{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}}</ref> 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}}.<ref name="Bowman_2008" />

== Extramitochondrial localisation ==

Cytochrome c is widely believed to be localised solely in the mitochondrial intermembrane space under normal physiological conditions.<ref name="pmid9242927">{{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}}</ref> 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.<ref name="pmid9558479">{{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}}</ref> 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.<ref name="pmid24054573">{{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}}</ref><ref name="pmid12815469">{{Cite journal |vauthors=Waterhouse NJ, [[Joseph Trapani (immunologist)|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}}</ref>  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.<ref name="Soltys_2001">{{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}}</ref> 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 [[vacuole]]s and in the acinar [[Lumen (anatomy)|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.<ref name="Soltys_2001" /> Besides cytochrome c, extramitochondrial localisation has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.<ref name="pmid18575266">{{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}}</ref><ref name="pmid16133117">{{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}}</ref><ref name="Soltys_2000">{{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}}</ref> This raises the possibility of the existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.<ref name="Soltys_2000" /><ref name="pmid10322429">{{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}}</ref>

== Applications ==

=== Superoxide detection ===

[[File:Peroxynitrous-acid-2D.svg|thumb|[[Peroxynitrous acid]]]]

Cytochrome c has been used to detect peroxide production in biological systems. As superoxide is produced, the number of oxidised cytochrome c<sup>3+</sup> increases, and reduced cytochrome c<sup>2+</sup> decreases.<ref>{{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}}</ref> However, superoxide is often produced with nitric oxide. In the presence of nitric oxide, the reduction of cytochrome c<sup>3+</sup> is inhibited.<ref name = "Thomson_1995">{{Cite journal |vauthors=Thomson L, Trujillo M, Telleri R, Radi R |date=June 1995 |title=Kinetics of cytochrome c<sup>2+</sup> 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}}</ref> 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.<ref name="Thomson_1995" /> 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.<ref>{{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}}</ref>

=== As an enzyme for catalytic activity ===
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.<ref>{{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}}</ref><ref name="Benson_2019">{{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}}</ref> Inspired from natural examples of enzyme encapsulation in protein-based cage structures (Example: Carboxysomes, Ferritin, and Encapsulin), Cytochrome C was encapsulated in a 9&nbsp;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.<ref>{{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}}</ref>

== See also ==
* [[Cytochrome c oxidase]]
* [[Methanol dehydrogenase (cytochrome c)]]

== References ==
{{Reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{Cite journal |vauthors=Kumarswamy R, Chandna S |date=February 2009 |title=Putative partners in Bax mediated cytochrome-c release: ANT, CypD, VDAC or none of them? |journal=Mitochondrion |volume=9 |issue=1 |pages=1–8 |doi=10.1016/j.mito.2008.10.003 |pmid=18992370}}
* {{Cite journal |vauthors=Skulachev VP |date=February 1998 |title=Cytochrome c in the apoptotic and antioxidant cascades |journal=FEBS Letters |volume=423 |issue=3 |pages=275–80 |doi=10.1016/S0014-5793(98)00061-1 |pmid=9515723 |s2cid=10267410}}
* {{Cite journal |vauthors=Mannella CA |year=1998 |title=Conformational changes in the mitochondrial channel protein, VDAC, and their functional implications |journal=Journal of Structural Biology |volume=121 |issue=2 |pages=207–18 |doi=10.1006/jsbi.1997.3954 |pmid=9615439}}
* {{Cite journal |vauthors=Ferri KF, Jacotot E, Blanco J, Esté JA, Kroemer G |year=2000 |title=Mitochondrial control of cell death induced by HIV-1-encoded proteins |journal=Annals of the New York Academy of Sciences |volume=926 |issue=1 |pages=149–64 |bibcode=2000NYASA.926..149F |doi=10.1111/j.1749-6632.2000.tb05609.x |pmid=11193032 |s2cid=21997163}}
* {{Cite journal |vauthors=Britton RS, Leicester KL, Bacon BR |date=October 2002 |title=Iron toxicity and chelation therapy |journal=International Journal of Hematology |volume=76 |issue=3 |pages=219–28 |doi=10.1007/BF02982791 |pmid=12416732 |s2cid=22572183}}
* {{Cite journal |vauthors=Haider N, Narula N, Narula J |date=December 2002 |title=Apoptosis in heart failure represents programmed cell survival, not death, of cardiomyocytes and likelihood of reverse remodeling |journal=Journal of Cardiac Failure |volume=8 |issue=6 Suppl |pages=S512–7 |doi=10.1054/jcaf.2002.130034 |pmid=12555167}}
* {{Cite journal |vauthors=Castedo M, Perfettini JL, Andreau K, Roumier T, Piacentini M, Kroemer G |date=December 2003 |title=Mitochondrial apoptosis induced by the HIV-1 envelope |journal=Annals of the New York Academy of Sciences |volume=1010 |issue=1 |pages=19–28 |bibcode=2003NYASA1010...19C |doi=10.1196/annals.1299.004 |pmid=15033690 |s2cid=37073602}}
* {{Cite journal |vauthors=Ng S, Smith MB, Smith HT, Millett F |date=November 1977 |title=Effect of modification of individual cytochrome c lysines on the reaction with cytochrome b5 |journal=Biochemistry |volume=16 |issue=23 |pages=4975–8 |doi=10.1021/bi00642a006 |pmid=199233}}
* {{Cite journal |vauthors=Lynch SR, Sherman D, Copeland RA |date=January 1992 |title=Cytochrome c binding affects the conformation of cytochrome a in cytochrome c oxidase |journal=The Journal of Biological Chemistry |volume=267 |issue=1 |pages=298–302 |doi=10.1016/S0021-9258(18)48493-1 |pmid=1309738 |doi-access=free}}
* {{Cite journal |vauthors=Garber EA, Margoliash E |date=February 1990 |title=Interaction of cytochrome c with cytochrome c oxidase: an understanding of the high- to low-affinity transition |journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics |volume=1015 |issue=2 |pages=279–87 |doi=10.1016/0005-2728(90)90032-Y |pmid=2153405}}
* {{Cite journal |vauthors=Bedetti CD |date=May 1985 |title=Immunocytochemical demonstration of cytochrome c oxidase with an immunoperoxidase method: a specific stain for mitochondria in formalin-fixed and paraffin-embedded human tissues |journal=The Journal of Histochemistry and Cytochemistry |volume=33 |issue=5 |pages=446–52 |doi=10.1177/33.5.2580882 |pmid=2580882 |doi-access=free}}
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* {{Cite journal |vauthors=Evans MJ, Scarpulla RC |date=December 1988 |title=The human somatic cytochrome c gene: two classes of processed pseudogenes demarcate a period of rapid molecular evolution |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=85 |issue=24 |pages=9625–9 |bibcode=1988PNAS...85.9625E |doi=10.1073/pnas.85.24.9625 |pmc=282819 |pmid=2849112 |doi-access=free}}
* {{Cite journal |vauthors=Passon PG, Hultquist DE |date=July 1972 |title=Soluble cytochrome b 5 reductase from human erythrocytes |journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics |volume=275 |issue=1 |pages=62–73 |doi=10.1016/0005-2728(72)90024-2 |pmid=4403130 |hdl-access=free |hdl=2027.42/34070}}
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* {{Cite journal |vauthors=Smith HT, Ahmed AJ, Millett F |date=May 1981 |title=Electrostatic interaction of cytochrome c with cytochrome c1 and cytochrome oxidase |journal=The Journal of Biological Chemistry |volume=256 |issue=10 |pages=4984–90 |doi=10.1016/S0021-9258(19)69355-5 |pmid=6262312 |doi-access=free}}
* {{Cite journal |vauthors=Geren LM, Millett F |date=October 1981 |title=Fluorescence energy transfer studies of the interaction between adrenodoxin and cytochrome c |journal=The Journal of Biological Chemistry |volume=256 |issue=20 |pages=10485–9 |doi=10.1016/S0021-9258(19)68647-3 |pmid=6270113 |doi-access=free}}
* {{Cite journal |vauthors=Favre B, Zolnierowicz S, Turowski P, Hemmings BA |date=June 1994 |title=The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo |journal=The Journal of Biological Chemistry |volume=269 |issue=23 |pages=16311–7 |doi=10.1016/S0021-9258(17)34009-7 |pmid=8206937 |doi-access=free}}
* {{Cite journal |vauthors=Gao B, Eisenberg E, Greene L |date=July 1996 |title=Effect of constitutive 70-kDa heat shock protein polymerization on its interaction with protein substrate |journal=The Journal of Biological Chemistry |volume=271 |issue=28 |pages=16792–7 |doi=10.1074/jbc.271.28.16792 |pmid=8663341 |doi-access=free}}
{{refend}}

== External links ==
{{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]]