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{{Infobox_gene}}
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[[File:Cytochrome c image 2.png|thumb|Heme prosthetic group of cytochrome c, consisting of a rigid porphyrin ring coordinated with an iron atom. ]]
| require_manual_inspection = no
The '''cytochrome complex''', or '''cyt ''c''''' is a small [[hemeprotein]] found loosely associated with the [[inner mitochondrial membrane|inner membrane]] of the [[mitochondrion]]. It belongs to the [[cytochrome c family]] of proteins. Cytochrome c is highly [[Water soluble|water-soluble]], unlike other [[cytochrome]]s, and is an essential component of the [[electron transport chain]], where it carries one electron. It is capable of undergoing [[oxidation]] and [[redox|reduction]], but does not bind [[oxygen]]. It transfers electrons between [[Coenzyme Q - cytochrome c reductase|Complexes III]] (Coenzyme Q – Cyt C reductase) and [[cytochrome c oxidase|IV]] (Cyt C oxidase). 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/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54205| accessdate = }}</ref><ref name="pmid11790791">{{cite journal | vauthors = Tafani M, Karpinich NO, Hurster KA, Pastorino JG, Schneider T, Russo MA, Farber JL | 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 | date = March 2002 | pmid = 11790791 | doi = 10.1074/jbc.M111350200 }}</ref>
| update_protein_box = yes
| update_summary = yes
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}}<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = Cytochrome c.png
| image_source = Cytochrome ''c'' with heme
| Name = Cytochrome c, somatic
| HGNCid = 19986
| Symbol = CYCS
| AltSymbols =; HCS; CYC
| OMIM = 123970
| ECnumber = 
| Homologene = 68675
| MGIid = 88578
| GeneAtlas_image1 = PBB_GE_CYCS_208905_at_tn.png
| Function = {{GNF_GO|id=GO:0000158 |text = protein phosphatase type 2A activity}} {{GNF_GO|id=GO:0005506 |text = iron ion binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0020037 |text = heme binding}} {{GNF_GO|id=GO:0045155 |text = electron transporter, transferring electrons from CoQH2-cytochrome c reductase complex and cytochrome c oxidase complex activity}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
  | Component = {{GNF_GO|id=GO:0000159 |text = protein phosphatase type 2A complex}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0005746 |text = mitochondrial respiratory chain}} {{GNF_GO|id=GO:0005758 |text = mitochondrial intermembrane space}} {{GNF_GO|id=GO:0005829 |text = cytosol}}
| Process = {{GNF_GO|id=GO:0006118 |text = electron transport}} {{GNF_GO|id=GO:0006309 |text = DNA fragmentation during apoptosis}} {{GNF_GO|id=GO:0006810 |text = transport}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0008635 |text = caspase activation via cytochrome c}} {{GNF_GO|id=GO:0045333 |text = cellular respiration}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 54205
    | Hs_Ensembl = ENSG00000172115
    | Hs_RefseqProtein = NP_061820
    | Hs_RefseqmRNA = NM_018947
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 7
    | Hs_GenLoc_start = 25124802
    | Hs_GenLoc_end = 25131480
    | Hs_Uniprot = P99999
    | Mm_EntrezGene = 13063
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = XM_975140
    | Mm_RefseqProtein = XP_980234
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
{{SI}}


== Species distribution ==


==Overview==
Cytochrome c is a highly conserved protein across the spectrum of species, found in plants, animals, 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 |url=https://www.uniprot.org/uniprot/P99999#section_seq |title=Cytochrome c – Homo sapiens (Human) |publisher=UniProt Consortium  |work=P99999 |quote=mass is 11,749 Daltons}}</ref> makes it useful in studies of [[cladistics]].<ref name="pmid14077496">{{cite journal | vauthors = Margoliash E | 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 | date = October 1963 | pmid = 14077496 | pmc = 221244 | doi = 10.1073/pnas.50.4.672 }}</ref> The cytochrome c molecule has been studied for the glimpse it gives into evolutionary biology.
'''Cytochrome ''c''''', or '''cyt ''c''''' (horse heart: [[Protein data bank|PDB]] [http://www.rcsb.org/pdb/cgi/explore.cgi?pid=233461034608315&page=0&pdbId=1HRC 1HRC]) is a small [[heme]] [[protein]] found loosely associated with the inner membrane of the [[mitochondrion]]. It is a soluble protein, unlike other [[cytochrome]]s, and is an essential component of the [[electron transfer chain]], where it carries one electron. It is capable of undergoing [[oxidation]] and [[redox|reduction]], but does not bind [[oxygen]]. It transfers electrons between [[Coenzyme Q - cytochrome c reductase|Complexes III]] and [[cytochrome c oxidase|IV]]. It belongs to [[cytochrome c family]] of proteins.


==Variation==
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">[http://www.indiana.edu/~ensiweb/lessons/molb.ws.pdf Amino acid sequences in cytochrome c proteins from different species], adapted from Strahler, Arthur; Science and Earth History, 1997. page 348.</ref> The sequences of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs more from that of horses.<ref name="isbn978-1-4051-5089-7">{{cite book | vauthors = Lurquin PF, Stone L, Cavalli-Sforza LL | title = Genes, culture, and human evolution: a synthesis |publisher=Blackwell | location = Oxford | year = 2007 | page = 79 | isbn = 978-1-4051-5089-7 | url = https://books.google.com/books?id=zdeWdF_NQhEC&pg=PA79&lpg=PA79&dq=chimpanzee+rhesus+cytochrome+c#PPA79,M1}}</ref>
[[Image:Cytochrome C.PNG|thumb|left|150px|Cytochrome ''c'', heme shown in red.]]


Cytochrome c is a highly conserved protein across the spectrum of species, found in plants, animals, and many unicellular organisms. This, along with its small size (molecular weight about 12,000 [[dalton (unit)|dalton]]s), makes it useful in studies of [[cladistics]]. Its primary structure consists of a chain of 100 [[amino acid]]s.
Cytochrome c has an amino acid sequence that is highly conserved in eukaryotes, differing 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  | last1 = Stryer | first1 = Lubert | name-list-format = vanc | title = Biochemistry | date = 1975 | publisher = W.H. Freeman and Company | location = San Francisco | isbn = 978-0-7167-0174-3 | page = 362 | edition = 1st }}</ref>  For example, human [[cytochrome oxidase]] reacts 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"/>


The cytochrome ''c'' molecule has been studied for the glimpse it gives into evolutionary biology.  Both [[chicken]]s and [[turkey]]s have the identical molecule (amino acid for amino acid) within their  mitochondria, whereas [[duck]]s possess molecules differing by one amino acid.  Similarly, both [[human]]s and [[chimpanzee]]s have the identical molecule, while [[rhesus monkeys]] possess cytochromes differing by one amino acid.
== Structure ==


==Functions==
[[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 | title = Microgravity protein crystallization | journal = NPJ Microgravity | volume = 1 | pages = 15010 | year = 2015 | pmid = 28725714 | doi = 10.1038/npjmgrav.2015.10 }}</ref>]]
Cytochrome ''c'' can catalyze several 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-sulphonic acid) ([[ABTS]]), 2-keto-4-thiomethyl butyric acid and 4-aminoantipyrine.


===Role in low level laser therapy===
Cytochrome c belongs to class I of the [[Cytochrome c family|c-type cytochrome family]]<ref name="pmid1646017">{{cite journal | vauthors = Ambler RP | title = Sequence variability in bacterial cytochromes c | journal = Biochimica et Biophysica Acta | volume = 1058 | issue = 1 | pages = 42–7 | date = May 1991 | pmid = 1646017 | doi = 10.1016/S0005-2728(05)80266-X }}</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 | title = Cytochrome c assembly | journal = IUBMB Life | volume = 65 | issue = 3 | pages = 209–16 | date = March 2013 | pmid = 23341334 | doi = 10.1002/iub.1123 }}</ref> This motif is located  towards the [[N-terminus]] of the [[peptide]] chain and it contains a histidine as the fifth ligand of the heme iron. The sixth 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 helix 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|url=https://pubs.acs.org/doi/10.1021/cr400479b|journal=Chemical Reviews|language=EN|volume=114|issue=8|pages=4366–4469|doi=10.1021/cr400479b|issn=0009-2665|pmc=4002152|pmid=24758379|via=}}</ref>
Cytochrome ''c'' is also suspected to be the functional complex in so called LLLT: [[Low-level laser therapy]].
In LLLT, laser light on the wavelength of 670 nanometer penetrates wounded and scarred tissue in order to increase cellular regeneration. Light of this wavelength appears capable of increasing activity of cytochrome ''c'', thus increasing metabolic activity and freeing up more energy for the cells to repair the tissue.{{Fact|date=April 2008}}


===Role in apoptosis===
=== Heme c ===
Cytochrome ''c'' is also an intermediate 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>{{cite journal |author=Liu X, Kim C, Yang J, Jemmerson R, Wang X |title=Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c |journal=Cell |volume=86 |issue=1 |pages=147-57 |year=1996 |pmid=8689682}}</ref>
. 


Cytochrome ''c'' is released by the mitochondria in response to pro-apoptotic stimuli. 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. This explains how the ER calcium release can reach cytotoxic levels.  This  release in turn activates [[caspase]] 9, a cysteine [[protease]].  Caspase 9 can then go on to activate caspases 3 and 7, which are responsible for destroying the cell from within.
[[File:Heme c.svg|thumb|Structure of heme c]]


==Classes==
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 | title = Role of heme in structural organization of cytochrome c probed by semisynthesis | journal = Biochemistry | volume = 38 | issue = 48 | pages = 15944–51 | date = November 1999 | pmid = 10625461 | doi = 10.1021/bi9919089 }}</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 | title = Effect of cytochrome c on the generation and elimination of O<sub>2</sub><sup>–</sup> and H<sub>2</sub>O<sub>2</sub> in mitochondria | journal = The Journal of Biological Chemistry | volume = 278 | issue = 4 | pages = 2356–60 | date = January 2003 | pmid = 12435729 | doi = 10.1074/jbc.M209681200 }}</ref>
In 1991 R. P. Ambler recognized four classes of cytochrome c:


*'''Class I''' includes the low­spin soluble cytochrome c of mitochondria and bacteria. It has the heme-­attachment site towards the N­ terminus of histidine and the sixth ligand provided by a methionine residue towards the C ­terminus.
=== Dipole moment ===


*'''Class II''' includes the high­spin cytochrome c'. It has the heme-m­attachment site closed to the N terminus of histidine.  
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 | 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 | date = April 1982 | pmid = 6279635 }}</ref><ref name = "Koppenol_1982">{{cite journal | vauthors = Koppenol WH, Rush JD, Mills JD, Margoliash E | title = The dipole moment of cytochrome c | journal = Molecular Biology and Evolution | volume = 8 | issue = 4 | pages = 545–58 | date = July 1991 | pmid = 1656165 | doi = 10.1093/oxfordjournals.molbev.a040659 }}</ref> The dipole moment of cytochrome c is a result 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 examples, vertebrate cytochromes c all have dipole moment of approximately 320 [[debye]] while cytochromes c of plants and insects have dipole moment of approximately 340 debye.<ref name="Koppenol_1982" />


*'''Class III''' comprises the low redox potential multiple­ heme cytochromes. The heme c groups are structurally and functionally nonequivalent and present different redox potentials in the range 0 to -400 mV.
== Function ==


*'''Class IV''' was originally created to hold the complex proteins that have other prosthetic groups as well as heme c.
Cytochrome c is a component of the [[electron transport chain]] in mitochondria. The [[heme]] group of cytochrome c accepts electrons from the [[Complex III|bc<sub>1</sub> complex]] and transfers electrons to the [[cytochrome c oxidase|complex IV]]. Cytochrome c is also involved in initiation of [[apoptosis]]. Upon release of cytochrome c to the cytoplasm, the protein binds [[APAF1|apoptotic protease activating factor-1 (Apaf-1)]].<ref name="entrez"/>


==References==
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-sulphonic acid) ([[ABTS]]), 2-keto-4-thiomethyl butyric acid and 4-aminoantipyrine.
<references/>


==Further reading==
A bacterial cytochrome ''c'' functions as a [[nitrite reductase]].<ref>{{cite book | first1 = Jörg | last1 = Schneider | first2 = Peter M.H. | last2 = Kroneck | editor1-first = Peter M.H. | editor1-last = Kroneck | editor2-first = Martha E. Sosa | editor2-last = Torres | title = The Metal-Driven Biogeochemistry of Gaseous Compounds in the Environment | series = Metal Ions in Life Sciences | volume = 14 | year = 2014 | publisher = Springer | chapter = Chapter 9: The Production of Ammonia by Multiheme Cytochromes c | pages = 211–236 | doi = 10.1007/978-94-017-9269-1_9 | name-list-format = vanc }}</ref>
{{refbegin | 2}}
 
{{PBB_Further_reading
=== Role in apoptosis ===
| citations =  
 
*{{cite journal  | author=Skulachev VP |title=Cytochrome c in the apoptotic and antioxidant cascades. |journal=FEBS Lett. |volume=423 |issue= 3 |pages= 275-80 |year= 1998 |pmid= 9515723 |doi=  }}
Cytochrome c also has 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 | title = Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c | journal = Cell | volume = 86 | issue = 1 | pages = 147–57 | date = July 1996 | pmid = 8689682 | doi = 10.1016/S0092-8674(00)80085-9 }}</ref>
*{{cite journal  | author=Mannella CA |title=Conformational changes in the mitochondrial channel protein, VDAC, and their functional implications. |journal=J. Struct. Biol. |volume=121 |issue= 2 |pages= 207-18 |year= 1998 |pmid= 9615439 |doi= 10.1006/jsbi.1997.3954 }}
 
*{{cite journal | author=Ferri KF, Jacotot E, Blanco J, ''et al.'' |title=Mitochondrial control of cell death induced by HIV-1-encoded proteins. |journal=Ann. N. Y. Acad. Sci. |volume=926 |issue= |pages= 149-64 |year= 2001 |pmid= 11193032 |doi= }}
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.
*{{cite journal | author=Britton RS, Leicester KL, Bacon BR |title=Iron toxicity and chelation therapy. |journal=Int. J. Hematol. |volume=76 |issue= 3 |pages= 219-28 |year= 2002 |pmid= 12416732 |doi= }}
 
*{{cite journal | author=Haider N, Narula N, Narula J |title=Apoptosis in heart failure represents programmed cell survival, not death, of cardiomyocytes and likelihood of reverse remodeling. |journal=J. Card. Fail. |volume=8 |issue= 6 Suppl |pages= S512-7 |year= 2003 |pmid= 12555167 |doi= 10.1054/jcaf.2002.130034 }}
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 | title = Cardiolipin oxidation sets cytochrome c free | journal = Nature Chemical Biology | volume = 1 | issue = 4 | pages = 188–9 | date = September 2005 | pmid = 16408030 | doi = 10.1038/nchembio0905-188 }}</ref>
*{{cite journal | author=Castedo M, Perfettini JL, Andreau K, ''et al.'' |title=Mitochondrial apoptosis induced by the HIV-1 envelope. |journal=Ann. N. Y. Acad. Sci. |volume=1010 |issue= |pages= 19-28 |year= 2004 |pmid= 15033690 |doi= }}
 
*{{cite journal | author=Ng S, Smith MB, Smith HT, Millett F |title=Effect of modification of individual cytochrome c lysines on the reaction with cytochrome b5. |journal=Biochemistry |volume=16 |issue= 23 |pages= 4975-8 |year= 1977 |pmid= 199233 |doi= }}
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 | 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 | date = December 2003 | pmid = 14608362 | doi = 10.1038/ncb1063 }}</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 are responsible for destroying the cell from within.
*{{cite journal | author=Lynch SR, Sherman D, Copeland RA |title=Cytochrome c binding affects the conformation of cytochrome a in cytochrome c oxidase. |journal=J. Biol. Chem. |volume=267 |issue= 1 |pages= 298-302 |year= 1992 |pmid= 1309738 |doi= }}
 
*{{cite journal | author=Garber EA, Margoliash E |title=Interaction of cytochrome c with cytochrome c oxidase: an understanding of the high- to low-affinity transition. |journal=Biochim. Biophys. Acta |volume=1015 |issue= 2 |pages= 279-87 |year= 1990 |pmid= 2153405 |doi= }}
=== Inhibition of apoptosis ===
*{{cite journal | author=Bedetti CD |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=J. Histochem. Cytochem. |volume=33 |issue= 5 |pages= 446-52 |year= 1985 |pmid= 2580882 |doi= }}
 
*{{cite journal | author=Tanaka Y, Ashikari T, Shibano Y, ''et al.'' |title=Construction of a human cytochrome c gene and its functional expression in Saccharomyces cerevisiae. |journal=J. Biochem. |volume=103 |issue= 6 |pages= 954-61 |year= 1988 |pmid= 2844747 |doi= }}
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 | 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 | date = June 1997 | pmid = 9192670 | pmc = 21263 | doi = 10.1073/pnas.94.13.6939 }}</ref> Another way that cells can control apoptosis is by phosphorylation of Tyr48 which would turn 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 | 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 | date = December 2011 | pmid = 21706253 | doi = 10.1007/s00775-011-0804-9 }}</ref>
*{{cite journal | author=Evans MJ, Scarpulla RC |title=The human somatic cytochrome c gene: two classes of processed pseudogenes demarcate a period of rapid molecular evolution. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 24 |pages= 9625-9 |year= 1989 |pmid= 2849112 |doi= }}
 
*{{cite journal | author=Passon PG, Hultquist DE |title=Soluble cytochrome b 5  reductase from human erythrocytes. |journal=Biochim. Biophys. Acta |volume=275 |issue= 1 |pages= 62-73 |year= 1972 |pmid= 4403130 |doi= }}
=== As an antioxidative enzyme ===
*{{cite journal | author=Dowe RJ, Vitello LB, Erman JE |title=Sedimentation equilibrium studies on the interaction between cytochrome c and cytochrome c peroxidase. |journal=Arch. Biochem. Biophys. |volume=232 |issue= 2 |pages= 566-73 |year= 1984 |pmid= 6087732 |doi= }}
 
*{{cite journal | author=Michel B, Bosshard HR |title=Spectroscopic analysis of the interaction between cytochrome c and cytochrome c oxidase. |journal=J. Biol. Chem. |volume=259 |issue= 16 |pages= 10085-91 |year= 1984 |pmid= 6088481 |doi= }}
[[File:Removal of O2- and H2O2 by cytochrome c.jpg|thumb|Removal of O<sup>2−</sup> and H<sub>2</sub>O<sub>2</sub> by cytochrome c]]
*{{cite journal | author=Broger C, Nałecz MJ, Azzi A |title=Interaction of cytochrome c with cytochrome bc1 complex of the mitochondrial respiratory chain. |journal=Biochim. Biophys. Acta |volume=592 |issue= 3 |pages= 519-27 |year= 1980 |pmid= 6251869 |doi= }}
 
*{{cite journal | author=Smith HT, Ahmed AJ, Millett F |title=Electrostatic interaction of cytochrome c with cytochrome c1 and cytochrome oxidase. |journal=J. Biol. Chem. |volume=256 |issue= 10 |pages= 4984-90 |year= 1981 |pmid= 6262312 |doi= }}
Cytochrome c is known to play a role in the [[electron transport chain]] and cell [[apoptosis]]. However, a recent study has shown that it can also act as an antioxidative enzyme in the mitochondria; and it does so by removing [[superoxide]] (O<sub>2</sub><sup>–</sup>) and [[hydrogen peroxide]] (H<sub>2</sub>O<sub>2</sub>) from [[mitochondria]].<ref name = "Bowman_2008">{{cite journal | vauthors = Bowman SE, Bren KL | title = The chemistry and biochemistry of heme c: functional bases for covalent attachment | journal = Natural Product Reports | volume = 25 | issue = 6 | pages = 1118–30 | date = December 2008 | pmid = 19030605 | pmc = 2654777 | doi = 10.1039/b717196j }}</ref> Therefore, not only is cytochrome c required in the mitochondria for cell respiration, but it is also needed in the mitochondria to limit the production of O<sub>2</sub><sup>–</sup> and H<sub>2</sub>O<sub>2</sub>.<ref name="Bowman_2008" />
*{{cite journal | author=Geren LM, Millett F |title=Fluorescence energy transfer studies of the interaction between adrenodoxin and cytochrome c. |journal=J. Biol. Chem. |volume=256 |issue= 20 |pages= 10485-9 |year= 1981 |pmid= 6270113 |doi=  }}
 
*{{cite journal | author=Favre B, Zolnierowicz S, Turowski P, Hemmings BA |title=The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo. |journal=J. Biol. Chem. |volume=269 |issue= 23 |pages= 16311-7 |year= 1994 |pmid= 8206937 |doi= }}
== Extramitochondrial localization ==
*{{cite journal | author=Gao B, Eisenberg E, Greene L |title=Effect of constitutive 70-kDa heat shock protein polymerization on its interaction with protein substrate. |journal=J. Biol. Chem. |volume=271 |issue= 28 |pages= 16792-7 |year= 1996 |pmid= 8663341 |doi= }}
 
}}
Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions.<ref name="pmid9242927">{{cite journal | vauthors = Neupert W | title = Protein import into mitochondria | journal = Annual Review of Biochemistry | volume = 66 | issue = | pages = 863–917 | year = 1997 | pmid = 9242927 | doi = 10.1146/annurev.biochem.66.1.863 }}</ref> The release of cytochrome-c from mitochondria to the cytosol, where it activates the [[caspase]] family of [[proteases]] is believed to be primary trigger leading to the onset of apoptosis.<ref name="pmid9558479">{{cite journal | vauthors = Kroemer G, Dallaporta B, Resche-Rigon M | title = The mitochondrial death/life regulator in apoptosis and necrosis | journal = Annual Review of Physiology | volume = 60 | issue = | pages = 619–42 | year = 1998 | pmid = 9558479 | doi = 10.1146/annurev.physiol.60.1.619 }}</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 | 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 | date = October 2013 | pmid = 24054573 | doi = 10.1016/j.talanta.2013.04.051 }}</ref><ref name="pmid12815469">{{cite journal | vauthors = Waterhouse NJ, Trapani JA | title = A new quantitative assay for cytochrome c release in apoptotic cells | journal = Cell Death and Differentiation | volume = 10 | issue = 7 | pages = 853–5 | date = July 2003 | pmid = 12815469 | doi = 10.1038/sj.cdd.4401263 }}</ref>  However, detailed immunoelectron microscopic 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 | title = Cytochrome-C localizes in secretory granules in pancreas and anterior pituitary | journal = Cell Biology International | volume = 25 | issue = 4 | pages = 331–8 | year = 2001 | pmid = 11319839 | doi = 10.1006/cbir.2000.0651 }}</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 [[vacuoles]] and in the acinar [[Lumen (anatomy)|lumen]]. The extramitochondrial localization of cytochrome c was shown to be specific as it was completely abolished upon adsorption of the primary antibody with the purified cytochrome c.<ref name="Soltys_2001" /> The presence of cytochrome-c outside of mitochondria at specific location under normal physiological conditions raises important questions concerning its cellular function and translocation mechanism.<ref name="Soltys_2001" /> Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.<ref name="pmid18575266">{{cite journal | vauthors = Gupta RS, Ramachandra NB, Bowes T, Singh B | title = Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10 | journal = Novartis Foundation Symposium | volume = 291 | issue = | pages = 59–68; discussion 69–73, 137–40 | year = 2008 | pmid = 18575266 | doi = 10.1002/9780470754030.ch5 | isbn = 978-0-470-75403-0 | series = Novartis Foundation Symposia }}</ref><ref name="pmid16133117">{{cite journal | vauthors = Sadacharan SK, Singh B, Bowes T, Gupta RS | title = Localization 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 | date = November 2005 | pmid = 16133117 | doi = 10.1007/s00418-005-0056-2 }}</ref><ref name="Soltys_2000">{{cite journal | vauthors = Soltys BJ, Gupta RS | title = Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective | journal = International Review of Cytology | volume = 194 | issue = | pages = 133–96 | year = 2000 | pmid = 10494626 | doi = 10.1016/s0074-7696(08)62396-7 | isbn = 978-0-12-364598-2 | series = International Review of Cytology }}</ref> This raises the possibility about 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 | title = Mitochondrial-matrix proteins at unexpected locations: are they exported? | journal = Trends in Biochemical Sciences | volume = 24 | issue = 5 | pages = 174–7 | date = May 1999 | pmid = 10322429 | doi = 10.1016/s0968-0004(99)01390-0 }}</ref>
{{refend}}
 
== 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 oxidized cytochrome c<sup>3+</sup> increases, and reduced cytochrome c<sup>2+</sup> decreases.<ref>{{cite journal | vauthors = McCord JM, Fridovich I | title = Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein) | journal = The Journal of Biological Chemistry | volume = 244 | issue = 22 | pages = 6049–55 | date = November 1969 | pmid = 5389100 }}</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 | 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 | date = June 1995 | pmid = 7786032 | doi = 10.1006/abbi.1995.1321 }}</ref> This leads to the oxidization of cytochrome c<sup>2+</sup> to cytochrome c<sup>3+</sup> 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</sub>O<sub>2</sub> and [[nitrogen dioxide]] NO<sub>2</sub> 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 transfer chain.<ref>{{cite journal | vauthors = Domazou AS, Gebicka L, Didik J, Gebicki JL, van der Meijden B, Koppenol WH | 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 | date = April 2014 | pmid = 24447894 | doi = 10.1016/j.freeradbiomed.2014.01.014 }}</ref>
 
== See also ==


* [[Cytochrome c oxidase]]


==Additional images==
== References ==
<gallery>
{{Reflist|33em}}
Image:ETC.PNG|ETC
Image:Etc2.png|ETC
</gallery>


==See also==
== Further reading ==
* [[PEGylation]]
{{refbegin|33em}}
* {{cite journal | vauthors = Kumarswamy R, Chandna S | 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 | date = February 2009 | pmid = 18992370 | doi = 10.1016/j.mito.2008.10.003 }}
* {{cite journal | vauthors = Skulachev VP | title = Cytochrome c in the apoptotic and antioxidant cascades | journal = FEBS Letters | volume = 423 | issue = 3 | pages = 275–80 | date = February 1998 | pmid = 9515723 | doi = 10.1016/S0014-5793(98)00061-1 }}
* {{cite journal | vauthors = Mannella CA | 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 | year = 1998 | pmid = 9615439 | doi = 10.1006/jsbi.1997.3954 }}
* {{cite journal | vauthors = Ferri KF, Jacotot E, Blanco J, Esté JA, Kroemer G | title = Mitochondrial control of cell death induced by HIV-1-encoded proteins | journal = Annals of the New York Academy of Sciences | volume = 926 | issue =  | pages = 149–64 | year = 2000 | pmid = 11193032 | doi = 10.1111/j.1749-6632.2000.tb05609.x }}
* {{cite journal | vauthors = Britton RS, Leicester KL, Bacon BR | title = Iron toxicity and chelation therapy | journal = International Journal of Hematology | volume = 76 | issue = 3 | pages = 219–28 | date = October 2002 | pmid = 12416732 | doi = 10.1007/BF02982791 }}
* {{cite journal | vauthors = Haider N, Narula N, Narula J | 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 | date = December 2002 | pmid = 12555167 | doi = 10.1054/jcaf.2002.130034 }}
* {{cite journal | vauthors = Castedo M, Perfettini JL, Andreau K, Roumier T, Piacentini M, Kroemer G | title = Mitochondrial apoptosis induced by the HIV-1 envelope | journal = Annals of the New York Academy of Sciences | volume = 1010 | issue =  | pages = 19–28 | date = December 2003 | pmid = 15033690 | doi = 10.1196/annals.1299.004 }}
* {{cite journal | vauthors = Ng S, Smith MB, Smith HT, Millett F | title = Effect of modification of individual cytochrome c lysines on the reaction with cytochrome b5 | journal = Biochemistry | volume = 16 | issue = 23 | pages = 4975–8 | date = November 1977 | pmid = 199233 | doi = 10.1021/bi00642a006 }}
* {{cite journal | vauthors = Lynch SR, Sherman D, Copeland RA | 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 | date = January 1992 | pmid = 1309738 | doi =  }}
* {{cite journal | vauthors = Garber EA, Margoliash E | title = Interaction of cytochrome c with cytochrome c oxidase: an understanding of the high- to low-affinity transition | journal = Biochimica et Biophysica Acta | volume = 1015 | issue = 2 | pages = 279–87 | date = February 1990 | pmid = 2153405 | doi = 10.1016/0005-2728(90)90032-Y }}
* {{cite journal | vauthors = Bedetti CD | 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 | date = May 1985 | pmid = 2580882 | doi = 10.1177/33.5.2580882 }}
* {{cite journal | vauthors = Tanaka Y, Ashikari T, Shibano Y, Amachi T, Yoshizumi H, Matsubara H | title = Construction of a human cytochrome c gene and its functional expression in Saccharomyces cerevisiae | journal = Journal of Biochemistry | volume = 103 | issue = 6 | pages = 954–61 | date = June 1988 | pmid = 2844747 | doi =  }}
* {{cite journal | vauthors = Evans MJ, Scarpulla RC | 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 | date = December 1988 | pmid = 2849112 | pmc = 282819 | doi = 10.1073/pnas.85.24.9625 }}
* {{cite journal | vauthors = Passon PG, Hultquist DE | title = Soluble cytochrome b 5 reductase from human erythrocytes | journal = Biochimica et Biophysica Acta | volume = 275 | issue = 1 | pages = 62–73 | date = July 1972 | pmid = 4403130 | doi = 10.1016/0005-2728(72)90024-2 }}
* {{cite journal | vauthors = Dowe RJ, Vitello LB, Erman JE | title = Sedimentation equilibrium studies on the interaction between cytochrome c and cytochrome c peroxidase | journal = Archives of Biochemistry and Biophysics | volume = 232 | issue = 2 | pages = 566–73 | date = August 1984 | pmid = 6087732 | doi = 10.1016/0003-9861(84)90574-5 }}
* {{cite journal | vauthors = Michel B, Bosshard HR | title = Spectroscopic analysis of the interaction between cytochrome c and cytochrome c oxidase | journal = The Journal of Biological Chemistry | volume = 259 | issue = 16 | pages = 10085–91 | date = August 1984 | pmid = 6088481 | doi =  }}
* {{cite journal | vauthors = Broger C, Nałecz MJ, Azzi A | title = Interaction of cytochrome c with cytochrome bc1 complex of the mitochondrial respiratory chain | journal = Biochimica et Biophysica Acta | volume = 592 | issue = 3 | pages = 519–27 | date = October 1980 | pmid = 6251869 | doi = 10.1016/0005-2728(80)90096-1 }}
* {{cite journal | vauthors = Smith HT, Ahmed AJ, Millett F | 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 | date = May 1981 | pmid = 6262312 | doi =  }}
* {{cite journal | vauthors = Geren LM, Millett F | 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 | date = October 1981 | pmid = 6270113 | doi =  }}
* {{cite journal | vauthors = Favre B, Zolnierowicz S, Turowski P, Hemmings BA | 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 | date = June 1994 | pmid = 8206937 | doi =  }}
* {{cite journal | vauthors = Gao B, Eisenberg E, Greene L | 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 | date = July 1996 | pmid = 8663341 | doi = 10.1074/jbc.271.28.16792 }}
{{refend}}


==External links==
== External links ==
* {{UMichOPM|families|superfamily|78}} - Calculated orientations of cytochromes c in the lipid bilayer
{{Commons category|Cytochrome c}}
* [http://macromoleculeinsights.com/cytochromec.php The Cytochrome c Protein]
* [https://www.youtube.com/watch?v=l4D0YxGi5Ec Apoptosis & Caspase 3] – PMAP [[The Proteolysis Map]]-animation
* {{MeshName|Cytochrome+c}}
* {{MeshName|Cytochrome+c}}


{{PDB Gallery|geneid=54205}}
{{Electron transport chain}}
{{Electron transport chain}}
 
{{Fas apoptosis signaling pathway}}


[[Category:Cellular respiration]]
[[Category:Cellular respiration]]
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[[Category:Programmed cell death]]
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[[Category:Peripheral membrane proteins]]
 
[[Category:Moonlighting proteins]]
[[de:Cytochrom c]]
[[es:Citocromo c]]
[[fr:Cytochrome C]]
[[it:Citocromo c]]
[[mk:Цитохром c]]
[[pl:Cytochrom c]]
[[pt:Citocromo c]]
[[ru:Цитохром c]]
 
{{WH}}
{{WS}}

Latest revision as of 14:03, 29 November 2018

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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File:Cytochrome c image 2.png
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 membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is highly water-soluble, unlike other cytochromes, and is an essential component of the electron transport chain, where it carries one electron. It is capable of undergoing oxidation and reduction, but does not bind oxygen. It transfers electrons between Complexes III (Coenzyme Q – Cyt C reductase) and IV (Cyt C oxidase). In humans, cytochrome c is encoded by the CYCS gene.[1][2]

Species distribution

Cytochrome c is a highly conserved protein across the spectrum of species, found in plants, animals, and many unicellular organisms. This, along with its small size (molecular weight about 12,000 daltons),[3] makes it useful in studies of cladistics.[4] The cytochrome c molecule 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.[5] The sequences of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs more from that of horses.[6]

Cytochrome c has an amino acid sequence that is highly conserved in eukaryotes, differing 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.[7] For example, human cytochrome oxidase reacts with wheat cytochrome c, in vitro; which held true for all pairs of species tested.[7] In addition, the redox potential of +0.25 volts is the same in all cytochrome c molecules studied.[7]

Structure

File:Tunafish cytochrome c crystals grown in microgravity.jpg
Tunafish cytochrome c crystals (~5 mm long) grown by liquid–liquid diffusion under microgravity conditions in outer space.[8]

Cytochrome c belongs to class I of the c-type cytochrome family[9] and contains a characteristic CXXCH (cysteine-any-any-cysteine-histidine) amino acid motif that binds heme.[10] This motif is located towards the N-terminus of the peptide chain and it contains a histidine as the fifth ligand of the heme iron. The sixth 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 helix respectively when referring to mitochondrial cytochrome c.[11]

Heme c

File:Heme c.svg
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.[12] 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.[13]

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.[14][15] The dipole moment of cytochrome c is a result from a cluster of negatively charged amino acid side chains at the "back" of the enzyme.[15] Despite variations in the number of bound heme groups and variations in sequence, the dipole moment of vertebrate cytochromes c is remarkably conserved. For examples, vertebrate cytochromes c all have dipole moment of approximately 320 debye while cytochromes c of plants and insects have dipole moment of approximately 340 debye.[15]

Function

Cytochrome c is a component of the electron transport chain in mitochondria. The heme group of cytochrome c accepts electrons from the bc1 complex and transfers electrons to the complex IV. Cytochrome c is also involved in initiation of apoptosis. Upon release of cytochrome c to the cytoplasm, the protein binds apoptotic protease activating factor-1 (Apaf-1).[1]

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-sulphonic acid) (ABTS), 2-keto-4-thiomethyl butyric acid and 4-aminoantipyrine.

A bacterial cytochrome c functions as a nitrite reductase.[16]

Role in apoptosis

Cytochrome c also has 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.[17]

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.

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.[18]

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.[19] 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 are responsible for destroying the cell from within.

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-xL.[20] Another way that cells can control apoptosis is by phosphorylation of Tyr48 which would turn cytochrome c into an anti-apoptotic switch.[21]

As an antioxidative enzyme

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

Cytochrome c is known to play a role in the electron transport chain and cell apoptosis. However, a recent study has shown that it can also act as an antioxidative enzyme in the mitochondria; and it does so by removing superoxide (O2–) and hydrogen peroxide (H2O2) from mitochondria.[22] Therefore, not only is cytochrome c required in the mitochondria for cell respiration, but it is also needed in the mitochondria to limit the production of O2– and H2O2.[22]

Extramitochondrial localization

Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions.[23] The release of cytochrome-c from mitochondria to the cytosol, where it activates the caspase family of proteases is believed to be primary trigger leading to the onset of apoptosis.[24] 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.[25][26] However, detailed immunoelectron microscopic 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.[27] 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 localization of cytochrome c was shown to be specific as it was completely abolished upon adsorption of the primary antibody with the purified cytochrome c.[27] The presence of cytochrome-c outside of mitochondria at specific location under normal physiological conditions raises important questions concerning its cellular function and translocation mechanism.[27] Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.[28][29][30] This raises the possibility about existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.[30][31]

Applications

Superoxide detection

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

Cytochrome c has been used to detect peroxide production in biological systems. As superoxide is produced, the number of oxidized cytochrome c3+ increases, and reduced cytochrome c2+ decreases.[32] However, superoxide is often produced with nitric oxide. In the presence of nitric oxide, the reduction of cytochrome c3+ is inhibited.[33] This leads to the oxidization of cytochrome c2+ to cytochrome c3+ by peroxynitrous acid, an intermediate made through the reaction of nitric oxide and superoxide.[33] Presence of peroxynitrite or H2O2 and nitrogen dioxide NO2 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 transfer chain.[34]

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: cytochrome c".
  2. ↑ Tafani M, Karpinich NO, Hurster KA, Pastorino JG, Schneider T, Russo MA, Farber JL (March 2002). "Cytochrome c release upon Fas receptor activation depends on translocation of full-length bid and the induction of the mitochondrial permeability transition". The Journal of Biological Chemistry. 277 (12): 10073–82. doi:10.1074/jbc.M111350200. PMID 11790791.
  3. ↑ "Cytochrome c – Homo sapiens (Human)". P99999. UniProt Consortium. mass is 11,749 Daltons
  4. ↑ Margoliash E (October 1963). "Primary structure and evolution of cytochrome c". Proceedings of the National Academy of Sciences of the United States of America. 50 (4): 672–9. doi:10.1073/pnas.50.4.672. PMC 221244. PMID 14077496.
  5. ↑ Amino acid sequences in cytochrome c proteins from different species, adapted from Strahler, Arthur; Science and Earth History, 1997. page 348.
  6. ↑ Lurquin PF, Stone L, Cavalli-Sforza LL (2007). Genes, culture, and human evolution: a synthesis. Oxford: Blackwell. p. 79. ISBN 978-1-4051-5089-7.
  7. ↑ 7.0 7.1 7.2 Stryer L (1975). Biochemistry (1st ed.). San Francisco: W.H. Freeman and Company. p. 362. ISBN 978-0-7167-0174-3.
  8. ↑ McPherson A, DeLucas LJ (2015). "Microgravity protein crystallization". NPJ Microgravity. 1: 15010. doi:10.1038/npjmgrav.2015.10. PMID 28725714.
  9. ↑ Ambler RP (May 1991). "Sequence variability in bacterial cytochromes c". Biochimica et Biophysica Acta. 1058 (1): 42–7. doi:10.1016/S0005-2728(05)80266-X. PMID 1646017.
  10. ↑ Mavridou DA, Ferguson SJ, Stevens JM (March 2013). "Cytochrome c assembly". IUBMB Life. 65 (3): 209–16. doi:10.1002/iub.1123. PMID 23341334.
  11. ↑ Liu J, Chakraborty S, Hosseinzadeh P, Yu Y, Tian S, Petrik I, Bhagi A, Lu Y (2014-04-23). "Metalloproteins Containing Cytochrome, Iron–Sulfur, or Copper Redox Centers". Chemical Reviews. 114 (8): 4366–4469. doi:10.1021/cr400479b. ISSN 0009-2665. PMC 4002152. PMID 24758379.
  12. ↑ Kang X, Carey J (November 1999). "Role of heme in structural organization of cytochrome c probed by semisynthesis". Biochemistry. 38 (48): 15944–51. doi:10.1021/bi9919089. PMID 10625461.
  13. ↑ Zhao Y, Wang ZB, Xu JX (January 2003). "Effect of cytochrome c on the generation and elimination of O2– and H2O2 in mitochondria". The Journal of Biological Chemistry. 278 (4): 2356–60. doi:10.1074/jbc.M209681200. PMID 12435729.
  14. ↑ Koppenol WH, Margoliash E (April 1982). "The asymmetric distribution of charges on the surface of horse cytochrome c. Functional implications". The Journal of Biological Chemistry. 257 (8): 4426–37. PMID 6279635.
  15. ↑ 15.0 15.1 15.2 Koppenol WH, Rush JD, Mills JD, Margoliash E (July 1991). "The dipole moment of cytochrome c". Molecular Biology and Evolution. 8 (4): 545–58. doi:10.1093/oxfordjournals.molbev.a040659. PMID 1656165.
  16. ↑ Schneider J, Kroneck PM (2014). "Chapter 9: The Production of Ammonia by Multiheme Cytochromes c". In Kroneck PM, Torres ME. The Metal-Driven Biogeochemistry of Gaseous Compounds in the Environment. Metal Ions in Life Sciences. 14. Springer. pp. 211–236. doi:10.1007/978-94-017-9269-1_9.
  17. ↑ Liu X, Kim CN, Yang J, Jemmerson R, Wang X (July 1996). "Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c". Cell. 86 (1): 147–57. doi:10.1016/S0092-8674(00)80085-9. PMID 8689682.
  18. ↑ Orrenius S, Zhivotovsky B (September 2005). "Cardiolipin oxidation sets cytochrome c free". Nature Chemical Biology. 1 (4): 188–9. doi:10.1038/nchembio0905-188. PMID 16408030.
  19. ↑ Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH (December 2003). "Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis". Nature Cell Biology. 5 (12): 1051–61. doi:10.1038/ncb1063. PMID 14608362.
  20. ↑ Kharbanda S, Pandey P, Schofield L, Israels S, Roncinske R, Yoshida K, Bharti A, Yuan ZM, Saxena S, Weichselbaum R, Nalin C, Kufe D (June 1997). "Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 94 (13): 6939–42. doi:10.1073/pnas.94.13.6939. PMC 21263. PMID 9192670.
  21. ↑ García-Heredia JM, Díaz-Quintana A, Salzano M, Orzáez M, Pérez-Payá E, Teixeira M, De la Rosa MA, Díaz-Moreno I (December 2011). "Tyrosine phosphorylation turns alkaline transition into a biologically relevant process and makes human cytochrome c behave as an anti-apoptotic switch". Journal of Biological Inorganic Chemistry. 16 (8): 1155–68. doi:10.1007/s00775-011-0804-9. PMID 21706253.
  22. ↑ 22.0 22.1 Bowman SE, Bren KL (December 2008). "The chemistry and biochemistry of heme c: functional bases for covalent attachment". Natural Product Reports. 25 (6): 1118–30. doi:10.1039/b717196j. PMC 2654777. PMID 19030605.
  23. ↑ Neupert W (1997). "Protein import into mitochondria". Annual Review of Biochemistry. 66: 863–917. doi:10.1146/annurev.biochem.66.1.863. PMID 9242927.
  24. ↑ Kroemer G, Dallaporta B, Resche-Rigon M (1998). "The mitochondrial death/life regulator in apoptosis and necrosis". Annual Review of Physiology. 60: 619–42. doi:10.1146/annurev.physiol.60.1.619. PMID 9558479.
  25. ↑ Loo JF, Lau PM, Ho HP, Kong SK (October 2013). "An aptamer-based bio-barcode assay with isothermal recombinase polymerase amplification for cytochrome-c detection and anti-cancer drug screening". Talanta. 115: 159–65. doi:10.1016/j.talanta.2013.04.051. PMID 24054573.
  26. ↑ Waterhouse NJ, Trapani JA (July 2003). "A new quantitative assay for cytochrome c release in apoptotic cells". Cell Death and Differentiation. 10 (7): 853–5. doi:10.1038/sj.cdd.4401263. PMID 12815469.
  27. ↑ 27.0 27.1 27.2 Soltys BJ, Andrews DW, Jemmerson R, Gupta RS (2001). "Cytochrome-C localizes in secretory granules in pancreas and anterior pituitary". Cell Biology International. 25 (4): 331–8. doi:10.1006/cbir.2000.0651. PMID 11319839.
  28. ↑ Gupta RS, Ramachandra NB, Bowes T, Singh B (2008). "Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10". Novartis Foundation Symposium. Novartis Foundation Symposia. 291: 59–68, discussion 69–73, 137–40. doi:10.1002/9780470754030.ch5. ISBN 978-0-470-75403-0. PMID 18575266.
  29. ↑ Sadacharan SK, Singh B, Bowes T, Gupta RS (November 2005). "Localization of mitochondrial DNA encoded cytochrome c oxidase subunits I and II in rat pancreatic zymogen granules and pituitary growth hormone granules". Histochemistry and Cell Biology. 124 (5): 409–21. doi:10.1007/s00418-005-0056-2. PMID 16133117.
  30. ↑ 30.0 30.1 Soltys BJ, Gupta RS (2000). "Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective". International Review of Cytology. International Review of Cytology. 194: 133–96. doi:10.1016/s0074-7696(08)62396-7. ISBN 978-0-12-364598-2. PMID 10494626.
  31. ↑ Soltys BJ, Gupta RS (May 1999). "Mitochondrial-matrix proteins at unexpected locations: are they exported?". Trends in Biochemical Sciences. 24 (5): 174–7. doi:10.1016/s0968-0004(99)01390-0. PMID 10322429.
  32. ↑ McCord JM, Fridovich I (November 1969). "Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein)". The Journal of Biological Chemistry. 244 (22): 6049–55. PMID 5389100.
  33. ↑ 33.0 33.1 Thomson L, Trujillo M, Telleri R, Radi R (June 1995). "Kinetics of cytochrome c2+ oxidation by peroxynitrite: implications for superoxide measurements in nitric oxide-producing biological systems". Archives of Biochemistry and Biophysics. 319 (2): 491–7. doi:10.1006/abbi.1995.1321. PMID 7786032.
  34. ↑ Domazou AS, Gebicka L, Didik J, Gebicki JL, van der Meijden B, Koppenol WH (April 2014). "The kinetics of the reaction of nitrogen dioxide with iron(II)- and iron(III) cytochrome c". Free Radical Biology & Medicine. 69: 172–80. doi:10.1016/j.freeradbiomed.2014.01.014. PMID 24447894.

Further reading

  • Kumarswamy R, Chandna S (February 2009). "Putative partners in Bax mediated cytochrome-c release: ANT, CypD, VDAC or none of them?". Mitochondrion. 9 (1): 1–8. doi:10.1016/j.mito.2008.10.003. PMID 18992370.
  • Skulachev VP (February 1998). "Cytochrome c in the apoptotic and antioxidant cascades". FEBS Letters. 423 (3): 275–80. doi:10.1016/S0014-5793(98)00061-1. PMID 9515723.
  • Mannella CA (1998). "Conformational changes in the mitochondrial channel protein, VDAC, and their functional implications". Journal of Structural Biology. 121 (2): 207–18. doi:10.1006/jsbi.1997.3954. PMID 9615439.
  • Ferri KF, Jacotot E, Blanco J, Esté JA, Kroemer G (2000). "Mitochondrial control of cell death induced by HIV-1-encoded proteins". Annals of the New York Academy of Sciences. 926: 149–64. doi:10.1111/j.1749-6632.2000.tb05609.x. PMID 11193032.
  • Britton RS, Leicester KL, Bacon BR (October 2002). "Iron toxicity and chelation therapy". International Journal of Hematology. 76 (3): 219–28. doi:10.1007/BF02982791. PMID 12416732.
  • Haider N, Narula N, Narula J (December 2002). "Apoptosis in heart failure represents programmed cell survival, not death, of cardiomyocytes and likelihood of reverse remodeling". Journal of Cardiac Failure. 8 (6 Suppl): S512–7. doi:10.1054/jcaf.2002.130034. PMID 12555167.
  • Castedo M, Perfettini JL, Andreau K, Roumier T, Piacentini M, Kroemer G (December 2003). "Mitochondrial apoptosis induced by the HIV-1 envelope". Annals of the New York Academy of Sciences. 1010: 19–28. doi:10.1196/annals.1299.004. PMID 15033690.
  • Ng S, Smith MB, Smith HT, Millett F (November 1977). "Effect of modification of individual cytochrome c lysines on the reaction with cytochrome b5". Biochemistry. 16 (23): 4975–8. doi:10.1021/bi00642a006. PMID 199233.
  • Lynch SR, Sherman D, Copeland RA (January 1992). "Cytochrome c binding affects the conformation of cytochrome a in cytochrome c oxidase". The Journal of Biological Chemistry. 267 (1): 298–302. PMID 1309738.
  • Garber EA, Margoliash E (February 1990). "Interaction of cytochrome c with cytochrome c oxidase: an understanding of the high- to low-affinity transition". Biochimica et Biophysica Acta. 1015 (2): 279–87. doi:10.1016/0005-2728(90)90032-Y. PMID 2153405.
  • Bedetti CD (May 1985). "Immunocytochemical demonstration of cytochrome c oxidase with an immunoperoxidase method: a specific stain for mitochondria in formalin-fixed and paraffin-embedded human tissues". The Journal of Histochemistry and Cytochemistry. 33 (5): 446–52. doi:10.1177/33.5.2580882. PMID 2580882.
  • Tanaka Y, Ashikari T, Shibano Y, Amachi T, Yoshizumi H, Matsubara H (June 1988). "Construction of a human cytochrome c gene and its functional expression in Saccharomyces cerevisiae". Journal of Biochemistry. 103 (6): 954–61. PMID 2844747.
  • Evans MJ, Scarpulla RC (December 1988). "The human somatic cytochrome c gene: two classes of processed pseudogenes demarcate a period of rapid molecular evolution". Proceedings of the National Academy of Sciences of the United States of America. 85 (24): 9625–9. doi:10.1073/pnas.85.24.9625. PMC 282819. PMID 2849112.
  • Passon PG, Hultquist DE (July 1972). "Soluble cytochrome b 5 reductase from human erythrocytes". Biochimica et Biophysica Acta. 275 (1): 62–73. doi:10.1016/0005-2728(72)90024-2. PMID 4403130.
  • Dowe RJ, Vitello LB, Erman JE (August 1984). "Sedimentation equilibrium studies on the interaction between cytochrome c and cytochrome c peroxidase". Archives of Biochemistry and Biophysics. 232 (2): 566–73. doi:10.1016/0003-9861(84)90574-5. PMID 6087732.
  • Michel B, Bosshard HR (August 1984). "Spectroscopic analysis of the interaction between cytochrome c and cytochrome c oxidase". The Journal of Biological Chemistry. 259 (16): 10085–91. PMID 6088481.
  • Broger C, Nałecz MJ, Azzi A (October 1980). "Interaction of cytochrome c with cytochrome bc1 complex of the mitochondrial respiratory chain". Biochimica et Biophysica Acta. 592 (3): 519–27. doi:10.1016/0005-2728(80)90096-1. PMID 6251869.
  • Smith HT, Ahmed AJ, Millett F (May 1981). "Electrostatic interaction of cytochrome c with cytochrome c1 and cytochrome oxidase". The Journal of Biological Chemistry. 256 (10): 4984–90. PMID 6262312.
  • Geren LM, Millett F (October 1981). "Fluorescence energy transfer studies of the interaction between adrenodoxin and cytochrome c". The Journal of Biological Chemistry. 256 (20): 10485–9. PMID 6270113.
  • Favre B, Zolnierowicz S, Turowski P, Hemmings BA (June 1994). "The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo". The Journal of Biological Chemistry. 269 (23): 16311–7. PMID 8206937.
  • Gao B, Eisenberg E, Greene L (July 1996). "Effect of constitutive 70-kDa heat shock protein polymerization on its interaction with protein substrate". The Journal of Biological Chemistry. 271 (28): 16792–7. doi:10.1074/jbc.271.28.16792. PMID 8663341.

External links

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