Nutrition Guide

Transmembrane ATPases import many of the metabolites necessary for cell metabolism and export toxins, wastes, and solutes that can hinder cellular processes. An important example is the sodium-potassium exchanger (or Na+/K+ATPase), which establishes the ionic concentration balance that maintains the cell potential. Another example is the hydrogen potassium ATPase (H+/K+ATPase or gastric proton pump) that acidifies the contents of the stomach.

Besides exchangers, other categories of transmembrane ATPase include co-transporters and pumps (however, some exchangers are also pumps). Some of these, like the Na+/K+ATPase, cause a net flow of charge, but others do not. These are called “electrogenic” and “nonelectrogenic” transporters, respectively.

ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate (ATP) into adenosine diphosphate (ADP) and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme (in most cases) harnesses to drive other chemical reactions that would not otherwise occur. This process is widely used in all known forms of life.

Some such enzymes are integral membrane proteins (anchored within biological membranes), and move solutes across the membrane. (These are called transmembrane ATPases).

ABC proteins have two nucleotide binding domains (areas where ATP binds to the protein and are hydrolysed to ADP) and two transmembrane domains (parts of the protein which span the membrane through which the substrate that’s to be transported passes, the substrate translocation pathway).

The ATP-binding cassette (ABC) family is a group of proteins which bind and hydrolyse ATP in order to transport substances across cellular membranes. They are prevalent in bacteria but are also in humans, and responsible for a diverse range of genetic diseases from Stargardt disease to Cystic Fibrosis.

The alternative oxidase is a integral membrane protein that is tightly bound to the inner mitochondrial membrane.[18] 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.[19] 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.[20] A 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 a tyrosine residue.[21]

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 organisms’ ability to resist these stresses, through reducing the level of oxidative stress.[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, as the alternative pathway generates less ATP, these fungicides are still effective in preventing spore germination, as this is an energy-intensive process.[17]

The alternative oxidase is an enzyme that forms part of the electron transport chain in plants, as well as some fungi, protists and possibly some animals.[1][2] Sequences similar to the plant oxidase have also been identified in bacterial genomes.[3][4]

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]