Editing Cytochrome c oxidase (section)

==Inhibition==

COX exists in three conformational states: fully oxidized (pulsed), partially reduced, and fully reduced. Each inhibitor has a high affinity to a different state. In the pulsed state, both the heme a{{sub|3}} and the Cu{{sub|B}} nuclear centers are oxidized; this is the conformation of the enzyme that has the highest activity. A two-electron reduction initiates a conformational change that allows oxygen to bind at the active site to the partially-reduced enzyme. Four electrons bind to COX to fully reduce the enzyme. Its fully reduced state, which consists of a reduced Fe{{sup|2+}} at the cytochrome a{{sub|3}} heme group and a reduced Cu{{sub|B}}{{sup|+}} binuclear center, is considered the inactive or resting state of the enzyme.<ref name="pmid17906319">{{cite journal | vauthors = Leavesley HB, Li L, Prabhakaran K, Borowitz JL, Isom GE | title = Interaction of cyanide and nitric oxide with cytochrome c oxidase: implications for acute cyanide toxicity | journal = Toxicological Sciences | volume = 101 | issue = 1 | pages = 101–11 | date = January 2008 | pmid = 17906319 | doi = 10.1093/toxsci/kfm254 | doi-access = free }}</ref>

[[Cyanide]], [[azide]], and [[carbon monoxide]]<ref name="pmid12969439">{{cite journal | vauthors = Alonso JR, Cardellach F, López S, Casademont J, Miró O | title = Carbon monoxide specifically inhibits cytochrome c oxidase of human mitochondrial respiratory chain | journal = Pharmacology & Toxicology | volume = 93 | issue = 3 | pages = 142–6 | date = September 2003 | pmid = 12969439 | doi = 10.1034/j.1600-0773.2003.930306.x | doi-access = free }}</ref> all bind to cytochrome c oxidase, inhibiting the protein from functioning and leading to the chemical [[asphyxiation]] of cells. Higher concentrations of molecular oxygen are needed to compensate for increasing inhibitor concentrations, leading to an overall decrease in metabolic activity in the cell in the presence of an inhibitor. Other ligands, such as nitric oxide and hydrogen sulfide, can also inhibit COX by binding to regulatory sites on the enzyme, reducing the rate of cellular respiration.<ref name = "pmid24059525">{{cite journal | vauthors = Nicholls P, Marshall DC, Cooper CE, Wilson MT | s2cid = 11554252 | title = Sulfide inhibition of and metabolism by cytochrome c oxidase | journal = Biochemical Society Transactions | volume = 41 | issue = 5 | pages = 1312–6 | date = October 2013 | pmid = 24059525 | doi = 10.1042/BST20130070 }}</ref>

Cyanide is a non-competitive inhibitor for COX,<ref>{{Cite book|url=https://books.google.com/books?id=HHaDGynAz1EC&q=cyanide+cytochrome+competitive&pg=PA130|title=Advanced Biology|last1=Roberts|first1=Michael|last2=Reiss|first2=Michael Jonathan|last3=Monger|first3=Grace|name-list-style=vanc|date=2000|publisher=Nelson Thornes|isbn=9780174387329|language=en|access-date=2020-10-25|archive-date=2022-02-24|archive-url=https://web.archive.org/web/20220224105346/https://books.google.com/books?id=HHaDGynAz1EC&q=cyanide+cytochrome+competitive&pg=PA130|url-status=live}}</ref><ref>{{Cite book|url=https://books.google.com/books?id=ASADBUVAiDUC&q=cyanide+cytochrome+competitive&pg=PA92|title=Biology: A Functional Approach|vauthors=Roberts MB|date=1986|publisher=Nelson Thornes|isbn=9780174480198|language=en|access-date=2020-10-25|archive-date=2022-02-24|archive-url=https://web.archive.org/web/20220224105345/https://books.google.com/books?id=ASADBUVAiDUC&q=cyanide+cytochrome+competitive&pg=PA92|url-status=live}}</ref> binding with high affinity to the partially-reduced state of the enzyme and hindering further reduction of the enzyme. In the pulsed state, cyanide binds slowly, but with high affinity. The ligand is posited to electrostatically stabilize both metals at once by positioning itself between them. A high nitric oxide concentration, such as one added exogenously to the enzyme, reverses cyanide inhibition of COX.<ref name= "pmid1144519">{{cite journal | vauthors = Jensen P, Wilson MT, Aasa R, Malmström BG | title = Cyanide inhibition of cytochrome c oxidase. A rapid-freeze e.p.r. investigation | journal = The Biochemical Journal | volume = 224 | issue = 3 | pages = 829–37 | date = December 1984 | pmid = 6098268 | pmc = 1144519 | doi = 10.1042/bj2240829 }}</ref>

[[Nitric oxide]] can reversibly<ref name= "pmid19461104">{{cite journal | vauthors = Gladwin MT, Shiva S | title = The ligand binding battle at cytochrome c oxidase: how NO regulates oxygen gradients in tissue | journal = Circulation Research | volume = 104 | issue = 10 | pages = 1136–8 | date = May 2009 | pmid = 19461104 | doi = 10.1161/CIRCRESAHA.109.198911 | doi-access = free }}</ref> bind to either metal ion in the binuclear center to be oxidized to nitrite. NO and CN{{sup|−}} will compete with oxygen to bind at the site, reducing the rate of cellular respiration. Endogenous NO, however, which is produced at lower levels, augments CN{{sup|−}} inhibition. Higher levels of NO, which correlate with the existence of more enzyme in the reduced state, lead to a greater inhibition of cyanide.<ref name = "pmid17906319"/> At these basal concentrations, NO inhibition of Complex IV is known to have beneficial effects, such as increasing oxygen levels in blood vessel tissues. The inability of the enzyme to reduce oxygen to water results in a buildup of oxygen, which can diffuse deeper into surrounding tissues.<ref name = "pmid19461104"/> NO inhibition of Complex IV has a larger effect at lower oxygen concentrations, increasing its utility as a vasodilator in tissues of need.<ref name = "pmid19461104"/>

[[Hydrogen sulfide]] will bind COX in a noncompetitive fashion at a regulatory site on the enzyme, similar to carbon monoxide. Sulfide has the highest affinity to either the pulsed or partially reduced states of the enzyme, and is capable of partially reducing the enzyme at the heme a{{sub|3}} center. It is unclear whether endogenous H{{sub|2}}S levels are sufficient to inhibit the enzyme. There is no interaction between hydrogen sulfide and the fully reduced conformation of COX.<ref name = "pmid24059525"/>

[[Methanol]] in [[denatured alcohol|methylated spirits]] is converted into [[formic acid]], which also inhibits the same oxidase system. High levels of ATP can [[allosteric inhibition|allosterically]] inhibit cytochrome c oxidase, binding from within the mitochondrial matrix.<ref name="pmid9363790">{{cite journal |vauthors=Arnold S, Kadenbach B | title = Cell respiration s controlled by ATP, an allosteric inhibitor of cytochrome-c oxidase. | journal = Eur J Biochem | pages = 350–354| date = October 1997 | doi = 10.1111/j.1432-1033.1997.t01-1-00350.x | pmid = 9363790 | volume=249| issue = 1 | doi-access = free }}</ref>