Editing Oxidative phosphorylation (section)

== Inhibitors ==
There are several well-known [[drug]]s and [[toxin]]s that inhibit oxidative phosphorylation. Although any one of these toxins inhibits only one enzyme in the electron transport chain, inhibition of any step in this process will halt the rest of the process. For example, if [[oligomycin]] inhibits ATP synthase, protons cannot pass back into the mitochondrion.<ref name=Joshi/> As a result, the proton pumps are unable to operate, as the gradient becomes too strong for them to overcome. NADH is then no longer oxidized and the citric acid cycle ceases to operate because the concentration of NAD<sup>+</sup> falls below the concentration that these enzymes can use.

Many site-specific inhibitors of the electron transport chain have contributed to the present knowledge of mitochondrial respiration. Synthesis of ATP is also dependent on the electron transport chain, so all site-specific inhibitors also inhibit ATP formation. The fish poison [[rotenone]], the barbiturate drug [[amobarbital|amytal]], and the antibiotic [[piericidin A]] inhibit NADH and coenzyme Q.<ref name="Satyanarayana_2002">{{Cite book|title=Biochemistry| vauthors = Satyanarayana U |date=2002 |publisher=Books and Allied |isbn=8187134801 |edition=2nd|location=Kolkata, India|oclc=71209231}}</ref>

Carbon monoxide, cyanide, hydrogen sulphide and azide effectively inhibit cytochrome oxidase. Carbon monoxide reacts with the reduced form of the cytochrome while cyanide and azide react with the oxidised form. An antibiotic, [[antimycin A]], and [[dimercaprol|British anti-Lewisite]], an antidote used against chemical weapons, are the two important inhibitors of the site between cytochrome B and C1.<ref name="Satyanarayana_2002" />

{| class="wikitable" style="margin-left: auto; margin-right: auto;"
!Compounds
!Use
! Site of action
!Effect on oxidative phosphorylation
|-
|[[Cyanide]]<br />[[carbon monoxide|Carbon&nbsp;monoxide]]<br />[[Azide]]<br />[[Hydrogen sulfide]]
|align="center" |Poisons
|Complex IV
|Inhibit the electron transport chain by binding more strongly than oxygen to the [[iron|Fe]]–[[copper|Cu]] center in cytochrome c oxidase, preventing the reduction of oxygen.<ref>{{cite journal | vauthors = Tsubaki M | title = Fourier-transform infrared study of cyanide binding to the Fea3-CuB binuclear site of bovine heart cytochrome c oxidase: implication of the redox-linked conformational change at the binuclear site | journal = Biochemistry | volume = 32 | issue = 1 | pages = 164–173 | date = January 1993 | pmid = 8380331 | doi = 10.1021/bi00052a022 }}</ref>
|-
|[[Oligomycin]]
|align="center" |[[Antibiotic]]
|Complex V
||Inhibits ATP synthase by blocking the flow of protons through the F<sub>o</sub> subunit.<ref name=Joshi>{{cite journal | vauthors = Joshi S, Huang YG | title = ATP synthase complex from bovine heart mitochondria: the oligomycin sensitivity conferring protein is essential for dicyclohexyl carbodiimide-sensitive ATPase | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1067 | issue = 2 | pages = 255–258 | date = August 1991 | pmid = 1831660 | doi = 10.1016/0005-2736(91)90051-9 }}</ref>
|-
|[[Carbonyl cyanide m-chlorophenyl hydrazone|CCCP]]<br />[[2,4-Dinitrophenol]]
|align="center" |Poisons, weight-loss<ref group="N">DNP was extensively used as an [[anti-obesity medication]] in the 1930s but was ultimately discontinued due to its dangerous side effects. However, illicit use of the drug for this purpose continues today. See [[2,4-Dinitrophenol#Dieting aid]] for more information.</ref>
| Inner membrane
||[[Ionophore]]s that disrupt the proton gradient by carrying protons across a membrane. This ionophore [[uncouples]] proton pumping from ATP synthesis because it carries protons across the inner mitochondrial membrane.<ref>{{cite conference | vauthors = Heytler PG | title = Biomembranes Part F: Bioenergetics: Oxidative Phosphorylation | chapter = Uncouplers of oxidative phosphorylation | volume = 55 | pages = 462–472 | year = 1979 | pmid = 156853 | doi = 10.1016/0076-6879(79)55060-5 | isbn = 978-0-12-181955-2 | series = Methods in Enzymology | editor1= Sidney Fleischer | editor2= Lester Packer}}</ref>
|-
|[[Rotenone]]
|align="center" |[[Pesticide]]
|Complex I
||Prevents the transfer of electrons from complex I to ubiquinone by blocking the ubiquinone-binding site.<ref>{{cite journal | vauthors = Lambert AJ, Brand MD | title = Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I) | journal = The Journal of Biological Chemistry | volume = 279 | issue = 38 | pages = 39414–39420 | date = September 2004 | pmid = 15262965 | doi = 10.1074/jbc.M406576200 | s2cid = 26620903 | doi-access = free }}</ref>
|-
|[[Malonate]] and [[oxaloacetate]]
|align="center" | Poisons
|Complex II
||Competitive inhibitors of succinate dehydrogenase (complex II).<ref>{{cite journal | vauthors = Dervartanian DV, Veeger C | title = Studies on Succinate Dehydrogenase. I. Spectral Properties of the Purified Enzyme and Formation of Enzyme-Competitive Inhibitor Complexes | journal = Biochimica et Biophysica Acta (BBA) - Specialized Section on Enzymological Subjects | volume = 92 | issue = 2 | pages = 233–247 | date = November 1964 | pmid = 14249115 | doi = 10.1016/0926-6569(64)90182-8 }}</ref>
|-
|[[Antimycin A]]
|align="center" |[[Piscicide]]
|Complex III
||Binds to the Qi site of [[Coenzyme Q – cytochrome c reductase|cytochrome c reductase]], thereby inhibiting the [[oxidation]] of [[ubiquinol]].
|-
|}

Not all inhibitors of oxidative phosphorylation are toxins. In [[brown adipose tissue]], regulated proton channels called [[uncoupling protein]]s can uncouple respiration from ATP synthesis.<ref>{{cite journal | vauthors = Ricquier D, Bouillaud F | title = The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP | journal = The Biochemical Journal | volume = 345 | issue = Pt 2 | pages = 161–179 | date = January 2000 | pmid = 10620491 | pmc = 1220743 | doi = 10.1042/0264-6021:3450161 }}</ref> This rapid respiration produces heat, and is particularly important as a way of maintaining [[body temperature]] for [[hibernation|hibernating]] animals, although these proteins may also have a more general function in cells' responses to stress.<ref>{{cite journal | vauthors = Borecký J, Vercesi AE | title = Plant uncoupling mitochondrial protein and alternative oxidase: energy metabolism and stress | journal = Bioscience Reports | volume = 25 | issue = 3–4 | pages = 271–286 | year = 2005 | pmid = 16283557 | doi = 10.1007/s10540-005-2889-2 | s2cid = 18598358 }}</ref>