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 inhibition by the poison cyanide.[5]
This metabolic pathway leading to the alternative oxidase diverges from the cytochrome-linked electron transport chain at the ubiquinone pool.[6] Alternative pathway respiration only produces proton translocation at Complex 1 (NADH dehydrogenase) and so has a lower 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.[7][8] Although the benefit conferred by this activity remains uncertain, it may enhance an organism's ability to resist these stresses by maintaining the oxidized state of the upstream electron-transport components, thereby reducing the level of oxidative stress induced by overreduced electron carriers.[9]
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.[10][11] This major metabolic difference between the parasite and its human host has made the T. brucei alternative oxidase an attractive target for drug design.[12][13] Of the known inhibitors of alternative oxidases, the antibiotic ascofuranone inhibits the T. brucei enzyme and cures infection in mice.[14][15]
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 complex III, such as azoxystrobin, picoxystrobin and fluoxastrobin.[16] However, even though the alternative pathway generates less ATP, these fungicides are still effective in preventing spore germination, as this is an energy-intensive process.[17]
^McDonald A, Vanlerberghe G (2004). "Branched mitochondrial electron transport in the Animalia: presence of alternative oxidase in several animal phyla". IUBMB Life. 56 (6): 333–41. doi:10.1080/1521-6540400000876. PMID15370881.
^Atteia A, van Lis R, van Hellemond JJ, Tielens AG, Martin W, Henze K (2004). "Identification of prokaryotic homologues indicates an endosymbiotic origin for the alternative oxidases of mitochondria (AOX) and chloroplasts (PTOX)". Gene. 330: 143–8. doi:10.1016/j.gene.2004.01.015. PMID15087133.
^Moore AL, Siedow JN (1991). "The regulation and nature of the cyanide-resistant alternative oxidase of plant mitochondria". Biochim. Biophys. Acta. 1059 (2): 121–40. doi:10.1016/S0005-2728(05)80197-5. PMID1883834.
^Vanlerberghe GC, McIntosh L (1997). "Alternative oxidase: From Gene to Function". Annual Review of Plant Physiology and Plant Molecular Biology. 48: 703–734. doi:10.1146/annurev.arplant.48.1.703. PMID15012279.
^Ito Y, Saisho D, Nakazono M, Tsutsumi N, Hirai A (1997). "Transcript levels of tandem-arranged alternative oxidase genes in rice are increased by low temperature". Gene. 203 (2): 121–9. doi:10.1016/S0378-1119(97)00502-7. PMID9426242.
^Chaudhuri M, Ott RD, Hill GC (2006). "Trypanosome alternative oxidase: from molecule to function". Trends Parasitol. 22 (10): 484–91. doi:10.1016/j.pt.2006.08.007. PMID16920028.
^Minagawa N, Yabu Y, Kita K, Nagai K, Ohta N, Meguro K, Sakajo S, Yoshimoto A (1997). "An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei". Mol. Biochem. Parasitol. 84 (2): 271–80. doi:10.1016/S0166-6851(96)02797-1. PMID9084049.
^Yabu Y, Yoshida A, Suzuki T, Nihei C, Kawai K, Minagawa N, Hosokawa T, Nagai K, Kita K, Ohta N (2003). "The efficacy of ascofuranone in a consecutive treatment on Trypanosoma brucei brucei in mice". Parasitol. Int. 52 (2): 155–64. doi:10.1016/S1383-5769(03)00012-6. PMID12798927.
^Miguez M, Reeve C, Wood PM, Hollomon DW (2004). "Alternative oxidase reduces the sensitivity of Mycosphaerella graminicola to QOI fungicides". Pest Manag. Sci. 60 (1): 3–7. doi:10.1002/ps.837. PMID14727735.
^Avila-Adame C, Köller W (2003). "Impact of alternative respiration and target-site mutations on responses of germinating conidia of Magnaporthe grisea to Qo-inhibiting fungicides". Pest Manag. Sci. 59 (3): 303–9. doi:10.1002/ps.638. PMID12639047.
^Berthold DA, Andersson ME, Nordlund P (2000). "New insight into the structure and function of the alternative oxidase". Biochim. Biophys. Acta. 1460 (2–3): 241–54. doi:10.1016/S0005-2728(00)00149-3. PMID11106766.
