Arsenate Detoxification I (Glutaredoxin)

General Background While the jury is still out about whether Napoleon Bonaparte died of arsenic poisoning or cancer (367316), it is agreed by all that arsenic is a potent toxicant. Indeed, the results of exposure to high arsenic concentration in drinking water in West Bengal, India, and Bangladesh are considered by some to be the worst public health disaster in recent history. The form of arsenic influences the type and severity of toxicity. Arsenate (As^V) is a structural analog of phosphate, and inhibits phosphorylation processes. For example, ADP-arsenate spontaneously hydrolyzes, resulting in uncoupling of oxidative phosphorylation, while arsenite (As^III) has a very high affinity for thiol groups, and thus binds to and inhibits many key enzymes that have thiol groups in their active sites. In addition, inorganic arsenic is a potent carcinogen. Arsenate enters the cell via the phosphate transport systems. Both prokaryotes and eukaryotes reduce intracellular arsenate to arsenite. However, while prokaryotes can pump arsenite out of the cell by using a dedicated pump (see arsenate detoxification II (glutaredoxin) ), multicellular organisms require other means of getting rid of the metal. Certain mammals, including humans, continue by methylating the arsenite to several methylated forms that are excreted from the organism in the urine. About This Pathway Detoxification of inorganic arsenate often involves methylation. Methylation of arsenic compounds has been documented in many organisms, including bacteria, fungi, green plants, and higher organisms. The process is so common that in certain environments methylated arsenic species become the dominant form of arsenic. Because of the overwhelming diversity of methylated arsenic species that have been observed, and the scarcity of biochemical data, this pathway is limited to the methylation of inorganic arsenic in mammals. Arsenic detoxification in most mammals involves alternative steps of reduction and oxidative methylation. The end metabolites are methylarsonate , cacodylate , and dimethylarsinous acid , which are less reactive than arsenate and arsenite, and are excreted in the urine. The pathway starts with the reduction of arsenate to arsenite. Even though arsenite is more toxic than arsenate, this transformation is essential, since only arsenite can be methylated. Arsenite is methylated to methylarsonate, which in turn is reduced to methylarsonite and methylated to dimethylarsinate. Dimethylarsinate can be further reduced to dimethylarsinous acid. The reduction of arsenate to arsenite occurs in two routes: In the first route arsenate can be conjugated to ribose by the enzyme purine nucleoside phosphorylase (PNP), which accepts arsenate as an alternative substrate to its normal substrate, phosphate. The ribose-1-arsenate thus formed is converted to arsenite in the presence of dihydrolipoate, in a process that has not been fully characterized yet. A second route is the direct reduction by the enzyme glutathione transferase, ω class, an unusual ω-class glutathione-S-transferase. This enzyme is not specific, and is responsible for all the other reduction steps in this pathway. Another key enzyme in this pathway is Arsenite methyltransferase. This enzyme is responsible for the two methylation steps, accepting both arsenite and methylarsinate as substrates. The gene encoding the arsenic methyltransferase was initially identified in rat, and subsequently in other mammals, including humans (15808521) . It is interesting to note that some mammals, including certain primates, do not methylate arsenite (10328340). In chimpanzees the most likely cause is a deletion within the AS3MT gene, encoding arsenic methyltransferase.