Structural insights into the alternative oxidases: are all oxidases made equal?

Abstract

The alternative oxidases (AOXs) are ubiquinol-oxidoreductases that are members of the diiron carboxylate superfamily. They are not only ubiquitously distributed within the plant kingdom but also found in increasing numbers within the fungal, protist, animal and prokaryotic kingdoms. Although functions of AOXs are highly diverse in general, they tend to play key roles in thermogenesis, stress tolerance (through the management of radical oxygen species) and the maintenance of mitochondrial and cellular energy homeostasis. The best structurally characterised AOX is from In this review, we compare the structure of AOXs, created using homology modelling, from many important species in an attempt to explain differences in activity and sensitivity to AOX inhibitors. We discuss the implications of these findings not only for future structure-based drug design but also for the design of novel AOXs for gene therapy.

Mitochondria as a therapeutic target for common pathologies

“…NAD + is regenerated from NADH by reduction of dihydroxyacetone phosphate to glycerol 3-phosphate by cytosolic glycerol 3-phosphate dehydrogenase 249 . The glycerol 3-phosphate is then reoxidised by mitochondrial glycerol 3phosphate dehydrogenase (mG3PDH), thereby reducing mitochondrial CoQ to CoQH2 which in turn is reoxidised by oxygen, catalysed by the alternative oxidase (AOX) in the mitochondrial respiratory chain 243,250 . Trypansomatid mitochondria also contain an active FoF1-ATP synthase which acts in reverse as a proton pump to maintain the Δp that is essential to maintain mitochondrial protein import and biogenesis 251 .…”

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

“…CpAOX was reported to be inhibited by AF (188) 6 and the potential of AOX as a novel target for chemotherapy against C. parvum was further corroborated by the inhibition of in vitro growth of C. parvum by SHAM (2) and 8-hydroxyquinoline (71). 6 An AOX has also been reported to be present in other intestinal parasites such as B. hominis, 2,[6][7][8]23 where it was thought that AOX helps Blastocystis cope with oxygen stress conditions in the intestine of the host and avoid the formation of reactive oxygen species (ROS). 26 The presence of AOX in the opportunistic human pathogen C. albicans has also been reported.…”

“…An AOX has also been reported to be present in other intestinal parasites such as B . hominis , where it was thought that AOX helps Blastocystis cope with oxygen stress conditions in the intestine of the host and avoid the formation of reactive oxygen species (ROS) …”

“…13,18,62,126,159,160 Although TAO is the only AOX whose structure has been experimentally elucidated, this has allowed the comparative modeling of other AOX in the context of explaining differences in catalytic efficiency and inhibitor sensitivity. This has recently been expertly reviewed by May et al 7 They proposed that, although the active site and the structure of the hydrophobic cavity are highly conserved, the major differences in V max and, for instance, sensitivity to AF, can be attributed to differences in the hydrophobic tunnel giving access to the central cavity. first isolated by Ando et al 175 from an organism that was initially described as the phytopathogenic fungus Ascochyta visiae but has now been reidentified as Acremonium sclerotigenum.…”

Identification of the alternative oxidase gene and its expression in the copepod Tigriopus californicus

“…Knowledge about animal AOX also has applications in human and animal medicine. Comparative research may aid in the treatment of diseases caused by parasitic protists, where AOX is a current target of drug design (May et al, 2017). AOX research could lead to the development of anti-parasitic drugs that can be used to kill parasitic copepods that live on the skin of economically valuable fish species.…”