Arsenate phosphorylation, uncoupling

Arsenate (pentavalent) uncouples mitochondrial oxidative phosphorylation by a mechanism whereby arsenate substitutes for inorganic phosphate in the formation of ATP, with subsequent formation of an unstable arsenate ester that is hydrolyzed rapidly. This process is termed arsenolysis. 

Energy generation will be inhibited because arsenate will uncouple oxidation and phosphorylation. The arsenate will establish a small futile cycle that will shuttle between 3-phosphoglycerate and l-arseno-3-phosphoglycerate. If the conditions also are anaerobic, NADH will accumulate, and NAD will become unavailable for the continuation of sustained glycolysis. 

As a consequence, in the presence of arsenate oxidation of 3-phosphoglyceraldehyde continues but ATP synthesis ceases. Arsenate is said to uncouple phosphorylation from oxidation. Arsenate can also partially replace phosphate in stimulating the respiration of mitochondria and is an uncoupler of oxidative phosphorylation (Chapter 18). Enzymes that normally act on a phosphorylated substrate will usually catalyze a slow reaction of the corresponding unphosphorylated substrate in the presence of arsenate. Apparently, the arsenate ester of the substrate forms transiently on the enzyme surface, permitting the reaction to occur. 

Glycolysis proceeds in the presence of arsenate, but the ATP normally formed in the conversion of 1,3-bisphosphoglycerate into 3-phosphoglycerate is lost. Thus, arsenate uncouples oxidation and phosphorylation by forming a highly labile acyl arsenate. 

The toxicity of Sb is a function of the water solubility and the oxidation state of the Sb species under consideration. Antimony toxicity often parallels that of arsenic, although antimony salts are less readily absorbed than arsenic. It is presumed that antimony, like arsenic, complexes with sulfhydryl groups of essential enzymes and other proteins. By analogy, antimony can uncouple oxidative phosphorylation, which would inhibit the production of energy necessary for cellular functions. Antimony s trivalent compounds are more toxic than its pentavalent compounds. 

The dehydration of (/ )-2-hydroxyglutarate to glutaconate has been studied by Buckel and co-workers (229, 2S0), who have found that the syn elimination of ( )-2-hydroxyglutarate requires a prior activation of the enzyme from cell-free extracts of A. fermentans by ATP, NADH, and MgCl2. The enzymic reaction requires a dithiol, acetyl phosphate, and CoASH, as well as strictly anaerobic conditions, because the active enzyme is irreversibly inactivated on contact with oxygen. Evidence was presented that the adenylation of the protein may be a requisite for activation. Based on preliminary EPR studies and the inactivation of the enzymic reaction by hydroxylamine and uncouplers of oxidative phosphorylation (such as azide, arsenate, and 2,4-dinitrophenol), Schweiger and Buckel postulated a radical mechanism for 2-hydroxyglutarate dehydration via the hydroxyl radical (Scheme 53) (229). Hence, the ATP/NADH-dependent ac-... 

The biochemical action of arsenic herbicides is primarily interference in phosphorus metabolism. They probably kill plants be the uncoupling of oxidative phosphorylation and by the blocking of the enzymes containing suifhydryl groups. 

Arsenate, As04 , is an uncoupling reagent for oxidative phosphorylation, but unlike DNP it does not transport protons across the inner mitochondrial membrane. How might arsenate function as an uncoupler ... 

Most forms of soluble arsenic are toxic to living organisms. Arsenate, a phosphate analog, uncouples respiratory chain phosphorylation due to the facile... 

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