View source for Alternative oxidase

[[Image:AOX .png|thumb|right|460px|The alternative oxidase shown as part of the complete [[electron transport chain]]. UQ is [[coenzyme Q10|ubiquinol/ubiquinone]], C is [[cytochrome c]] and AOX is the alternative oxidase.]]
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==Overview==
The '''alternative oxidase''' is an enzyme that forms part of the [[electron transport chain]] in [[plant]]s, as well as some [[fungus|fungi]], [[protist]]s and possibly some [[animal]]s.<ref>{{cite journal |author=McDonald A, Vanlerberghe G |title=Branched mitochondrial electron transport in the Animalia: presence of alternative oxidase in several animal phyla |journal=IUBMB Life |volume=56 |issue=6 |pages=333-41 |year=2004 |pmid=15370881}}</ref><ref>{{cite journal |author=Sluse FE, Jarmuszkiewicz W |title=Alternative oxidase in the branched mitochondrial respiratory network: an overview on structure, function, regulation, and role |journal=Braz. J. Med. Biol. Res. |volume=31 |issue=6 |pages=733-47 |year=1998 |pmid=9698817}}</ref> Sequences similar to the plant oxidase have also been identified in [[bacteria]]l genomes.<ref>{{cite journal |author=McDonald AE, Amirsadeghi S, Vanlerberghe GC |title=Prokaryotic orthologues of mitochondrial alternative oxidase and plastid terminal oxidase |journal=Plant Mol. Biol. |volume=53 |issue=6 |pages=865-76 |year=2003 |pmid=15082931}}</ref><ref>{{cite journal |author=Atteia A, van Lis R, van Hellemond JJ, Tielens AG, Martin W, Henze K |title=Identification of prokaryotic homologues indicates an endosymbiotic origin for the alternative oxidases of mitochondria (AOX) and chloroplasts (PTOX) |journal=Gene |volume=330 |issue= |pages=143-8 |year=2004 |pmid=15087133}}</ref> 

The oxidase provides an alternative route for electrons passing through the electron transport chain to reduce oxygen. However, as several [[proton]]-pumping steps are bypassed in this alternative pathway, activation of the oxidase reduces ATP generation. This enzyme was first identified as a distinct oxidase pathway from [[cytochrome c oxidase]] as the alternative oxidase is resistant to [[enzyme inhibitor|inhibition]] by the poison [[cyanide]].<ref>{{cite journal |author=Moore AL, Siedow JN |title=The regulation and nature of the cyanide-resistant alternative oxidase of plant mitochondria |journal=Biochim. Biophys. Acta |volume=1059 |issue=2 |pages=121-40 |year=1991 |pmid=1883834}}</ref>

==Function==
This [[metabolic pathway]] leading to the alternative oxidase diverges from the cytochrome-linked electron transport chain at the [[coenzyme Q10|ubiquinone]] pool.<ref>{{cite journal |author=Juszczuk IM, Rychter AM |title=Alternative oxidase in higher plants |url=http://www.actabp.pl/pdf/4_2003/1257.pdf |journal=Acta Biochim. Pol. |volume=50 |issue=4 |pages=1257-71 |year=2003 |pmid=14740012}}</ref> Alternative pathway respiration only produces proton translocation at Complex 1 (NADH dehydrogenase) and so has a lower [[adenosine triphosphate|ATP]] yield than the full pathway. The expression of the alternative oxidase gene ''AOX'' is influenced by stresses such as cold, [[reactive oxygen species]] and infection by pathogens, as well as other factors that reduce electron flow through the cytochrome pathway of respiration.<ref>{{cite journal |author=Vanlerberghe GC, McIntosh L |title=Alternative oxidase: From Gene to Function |journal= |volume=48 |issue= |pages=703-734 |year=1997 |pmid=15012279}}</ref><ref>{{cite journal |author=Ito Y, Saisho D, Nakazono M, Tsutsumi N, Hirai A |title=Transcript levels of tandem-arranged alternative oxidase genes in rice are increased by low temperature |journal=Gene |volume=203 |issue=2 |pages=121-9 |year=1997 |pmid=9426242}}</ref> Although the benefit conferred by this activity remains uncertain, it may enhance an organisms' ability to resist these stresses, through reducing the level of [[oxidative stress]].<ref>{{cite journal |author=Maxwell DP, Wang Y, McIntosh L |title=The alternative oxidase lowers mitochondrial reactive oxygen production in plant cells |url=http://www.pnas.org/cgi/content/full/96/14/8271 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=14 |pages=8271-6 |year=1999 |pmid=10393984}}</ref>
[[Image:Azoxystrobin-2D-skeletal.png|thumb|250px|left|The [[fungicide]] azoxystrobin.]]
Unusually, the bloodstream form of the protozoan parasite ''[[Trypanosoma brucei]]'', which is the cause of [[sleeping sickness]], depends entirely on the alternative oxidase pathway for cellular respiration through its electron transport chain.<ref>{{cite journal |author=Chaudhuri M, Ott RD, Hill GC |title=Trypanosome alternative oxidase: from molecule to function |journal=Trends Parasitol. |volume=22 |issue=10 |pages=484-91 |year=2006 |pmid=16920028}}</ref><ref>{{cite journal |author=Clarkson AB, Bienen EJ, Pollakis G, Grady RW |title=Respiration of bloodstream forms of the parasite Trypanosoma brucei brucei is dependent on a plant-like alternative oxidase |url=http://www.jbc.org/cgi/reprint/264/30/17770.pdf |journal=J. Biol. Chem. |volume=264 |issue=30 |pages=17770-6 |year=1989 |pmid=2808350}}</ref> This major metabolic difference between the parasite and its human [[host (biology)|host]] has made the ''T. brucei'' alternative oxidase an attractive target for [[drug design]].<ref>{{cite journal |author=Nihei C, Fukai Y, Kita K |title=Trypanosome alternative oxidase as a target of chemotherapy |journal=Biochim. Biophys. Acta |volume=1587 |issue=2-3 |pages=234-9 |year=2002 |pmid=12084465}}</ref><ref>{{cite journal |author=Grady RW, Bienen EJ, Dieck HA, Saric M, Clarkson AB |title=N-n-alkyl-3,4-dihydroxybenzamides as inhibitors of the trypanosome alternative oxidase: activity in vitro and in vivo |url=http://aac.asm.org/cgi/reprint/37/5/1082.pdf |journal=Antimicrob. Agents Chemother. |volume=37 |issue=5 |pages=1082-5 |year=1993 |pmid=8517695}}</ref> Of the known inhibitors of alternative oxidases, the antibiotic [[ascofuranone]] inhibits the ''T. brucei'' enzyme and cures infection in mice.<ref>{{cite journal |author=Minagawa N, Yabu Y, Kita K, Nagai K, Ohta N, Meguro K, Sakajo S, Yoshimoto A |title=An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei |journal=Mol. Biochem. Parasitol. |volume=84 |issue=2 |pages=271-80 |year=1997 |pmid=9084049}}</ref><ref>{{cite journal |author=Yabu Y, Yoshida A, Suzuki T, Nihei C, Kawai K, Minagawa N, Hosokawa T, Nagai K, Kita K, Ohta N |title=The efficacy of ascofuranone in a consecutive treatment on Trypanosoma brucei brucei in mice |journal=Parasitol. Int. |volume=52 |issue=2 |pages=155-64 |year=2003 |pmid=12798927}}</ref>

In fungi, the ability of the alternative oxidase to bypass inhibition of parts of the electron transport chain can contribute to [[fungicide]] resistance. This is seen in the [[strobilurin]] fungicides that target [[Coenzyme Q - cytochrome c reductase|complex III]], such as azoxystrobin, picoxystrobin and fluoxastrobin.<ref>{{cite journal |author=Miguez M, Reeve C, Wood PM, Hollomon DW |title=Alternative oxidase reduces the sensitivity of Mycosphaerella graminicola to QOI fungicides |journal=Pest Manag. Sci. |volume=60 |issue=1 |pages=3-7 |year=2004 |pmid=14727735}}</ref> However, as the alternative pathway generates less ATP, these fungicides are still effective in preventing [[spore]] germination, as this is an energy-intensive process.<ref>{{cite journal |author=Avila-Adame C, Köller W |title=Impact of alternative respiration and target-site mutations on responses of germinating conidia of Magnaporthe grisea to Qo-inhibiting fungicides |journal=Pest Manag. Sci. |volume=59 |issue=3 |pages=303-9 |year=2003 |pmid=12639047}}</ref>

==Structure and mechanism==
The alternative oxidase is a [[integral membrane protein]] that is tightly bound to the inner mitochondrial membrane.<ref>{{cite journal |author=Berthold DA, Stenmark P |title=Membrane-bound diiron carboxylate proteins |journal=Annual review of plant biology |volume=54 |issue= |pages=497-517 |year=2003 |pmid=14503001}}</ref> The enzyme has been predicted to contain a coupled diiron center on the basis of a conserved sequence motif consisting of the proposed iron ligands, four [[glutamine]] and two [[histidine]] amino acid residues.<ref>{{cite journal |author=Berthold DA, Andersson ME, Nordlund P |title=New insight into the structure and function of the alternative oxidase |journal=Biochim. Biophys. Acta |volume=1460 |issue=2-3 |pages=241-54 |year=2000 |pmid=11106766}}</ref> The [[electron spin resonance]] study of ''[[Arabidopsis thaliana]]'' alternative oxidase AOX1a showed that the enzyme contains a hydroxo-bridged mixed-valent Fe(II)/Fe(III) binuclear [[iron]] center.<ref>{{cite journal |author=Berthold DA, Voevodskaya N, Stenmark P, Gräslund A, Nordlund P |title=EPR studies of the mitochondrial alternative oxidase. Evidence for a diiron carboxylate center |url=http://www.jbc.org/cgi/content/full/277/46/43608 |journal=J. Biol. Chem. |volume=277 |issue=46 |pages=43608-14 |year=2002 |pmid=12215444}}</ref> A [[enzyme catalysis|catalytic cycle]] has been proposed that involves this di-iron center and at least one transient protein-derived [[free radical]], which is probably formed on an invariant [[tyrosine]] residue.<ref>{{cite journal |author=Affourtit C, Albury MS, Crichton PG, Moore AL |title=Exploring the molecular nature of alternative oxidase regulation and catalysis |journal=FEBS Lett. |volume=510 |issue=3 |pages=121-6 |year=2002 |pmid=11801238}}</ref>

==See also==
* [[Metalloprotein]]
* [[Bioinorganic chemistry]]
* [[Cofactor]]

==References==
{{reflist|2}}

==External links==
* [http://www.chem.qmul.ac.uk/iubmb/etp/etp1t3.html Electron transport proteins]
* [http://www.ebi.ac.uk/interpro/DisplayIproEntry?ac=IPR002680 InterPro entry on alternative oxidases]
* {{MeshName|alternative+oxidase}}
* [http://www.tau.ac.il/~ecology/virtau/2-elitsur/ey.htm#AlternativeRespiration Alternative respiration] Root Research Introduction Virtual Course Seminar


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{{Diphenol family oxidoreductases}}
{{Electron transport chain}}
{{Cellular respiration}}


[[Category:Integral membrane proteins]]
[[Category:Cellular respiration]]
[[Category:Metabolism]]

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