Arsenite dehydrogenase

JW Legge, AW Turner. Bacterial oxidation of arsenite. III. Cell-free arsenite dehydrogenase. Aust J Biol Sci 7 496-503, 1954. 

Arsenite and mercuric ions react with the —SH groups of lipoic acid and inhibit pyruvate dehydrogenase, as... 

This mechanism is supported by the fact that every 3-oxoalkylarsonic acid studied also eliminated arsenite. First, 3-hyroxypropylarsonic acid proved to be a substrate for alcohol dehydrogenase from yeast, and similarly eliminated arsenite. Further, the oxidation by periodate of the HO—CH2—CHOH—CH2—CH2—As03H2, expected to produce 0=CH—CH2—CH2—As03H2 (another 3-oxoalkylarsonic acid), also yielded arsenite, and conditions that normally transaminate amino acids, when applied to the glutamate analogue HOOC—CH(—NH2)—... 

Petrick, J.S., Jagadish, B., Mash, E.A. and Aposhian, H.V. (2001) Monomethylarsonous acid (MMA(III)) and arsenite LD50 in hamsters and in vitro inhibition of pyruvate dehydrogenase. Chemical Research in Toxicology, 14(6), 651-56. 

Tang PT, Wang XP, Lu DS. 1992. Changes in lactate dehydrogenase isoenzymes of mitochondriaand microsomes in hepatic damage caused by phosphorus, sodium arsenite, and carbon tetrachloride. Zhongguo Yaolixue Yu Dulixue Zazhi 6(4) 292-296. 

Pyruvate produced by the glycolytic pathway may be transported into the mitochondria (via an antiport with OH"), where it is converted to acetyl-CoA by the action of the enzyme complex pyruvate dehydrogenase. The pertinent enzyme activities are pyruvate dehydrogenase (PD), lipoic acid acetyltransferase, and dihydrolipoic acid dehydrogenase. In addition, several cofactors are utilized thiamine pyrophosphate (TPP), lipoic acid, NAD+, Co A, and FAD. Only Co A and NAD+ are used in stoichiometric amounts, whereas the others are required in catalytic amounts. Arsenite and Hg2+ are inhibitors of this system. The overall reaction sequence may be represented by Figure 18.5. The NADH generated may enter the oxidative phosphorylation pathway to generate three ATP molecules per NADH molecule reduced. The reaction is practically irreversible its AGq = -9.4 kcal/mol. 

Other members of this family that have been structurally determined by X-ray diffraction include formate dehydrogenase (FDH), trimethylamine oxidase (TMAO), dissimilatory nitrate reductase(NAP), and most recently, arsenite oxidase (AsO). Only the distinctive points of their structures will be briefly described here. 

Fia. 2. Anaerobic reduction of pig heart lipoamide dehydrogenase in the presence of arsenite (27) 1, oxidized enzyme plus 1 mM arsenite 2, after 1X> equivalent NADH 3, after 23 equivalents NADH 4, after 33 equivalents NADH and 6, after XADase. 

Reduction of lipoamide dehydrogenase by NADH with arsenite present... 

Trivalent inorganic arsenicals, such as arsenite, readily react with sulfhydryl groups, such as GSH and cysteine (Scott et al, 1993 Delnomdedieu et al, 1994). The complex between arsenic and the vicinal sulfhydryl group is particularly strong. Arsenite inhibits pyruvate dehydrogenase (PDH) activity (Hu et al, 1998), perhaps by binding to the... 

Figure 17.20. Arsenite Poisoning. Arsenite inhibits the pyruvate dehydrogenase complex by inactivating the dihydrolipoamide component of the transacetylase. Some sulfhydryl reagents, such as 2,3-dimercaptoethanol, relieve the inhibition by forming a complex with the arsenite that can be excreted.

The answer is a. (Murray, pp 182-189. Scriver, pp 1521-1552. Sack, pp 121-138. Wilson, pp 287-317.) Fluoracetate can be converted to fluorocitrate, which is an inhibitor of aconitase. Arsenic is not a direct inhibitor, but arsenite is an inhibitor of lipoic acid-containing enzymes such as a-ketoglutarate dehydrogenase. Malonate, not malic acid, is an inhibitor of... 

---