Human Monomethylarsonic Acid (MMA^V) Reductase Is a Member of the Glutathione-S-transferase Superfamily

Abstract

The drinking of water containing large amounts of inorganic arsenic is a worldwide major public health problem because of arsenic carcinogenicity. Yet an understanding of the specific mechanism(s) of inorganic arsenic toxicity has been elusive. We have now partially purified the rate-limiting enzyme of inorganic arsenic metabolism, human liver MMA(V) reductase, using ion exchange, molecular exclusion, and hydroxyapatite chromatography. When SDS-beta-mercaptoethanol-PAGE was performed on the most purified fraction, seven protein bands were obtained. Each band was excised from the gel, sequenced by LC-MS/MS and identified according to the SWISS-PROT and TrEMBL Protein Sequence databases. Human liver MMA(V) reductase is 100% identical, over 92% of sequence that we analyzed, with the recently discovered human glutathione-S-transferase Omega class hGSTO 1-1. Recombinant human GSTO1-1 had MMA(V) reductase activity with K(m) and V(max) values comparable to those of human liver MMA(V) reductase. The partially purified human liver MMA(V) reductase had glutathione S-transferase (GST) activity. MMA(V) reductase activity was competitively inhibited by the GST substrate, 1-chloro 2,4-dinitrobenzene and also by the GST inhibitor, deoxycholate. Western blot analysis of the most purified human liver MMA(V) reductase showed one band when probed with hGSTO1-1 antiserum. We propose that MMA(V) reductase and hGSTO 1-1 are identical proteins.

Glutathione S-transferase polymorphisms: cancer incidence and therapy

“…GSTO1*A demonstrated a GSH-dependent reduction of dehydroascorbate, a function characteristic of glutaredoxins rather than GSTs (Board et al, 2000). This allele was first described as the human monomethylarsenic acid reductase, (MMA[V]), and is the rate-limiting enzyme of inorganic arsenic metabolism (Zakharyan et al, 2001). Thioltransferase activity differs among the GSTO1*A-C polymorphisms and may contribute to an individual's ability to metabolize arsenic (Tanaka- Kagawa et al, 2003).…”

Glutathione Transferase Omega 1 Catalyzes the Reduction of S-(Phenacyl)glutathiones to Acetophenones

“…Two human omega-class genes have been characterized, and their RNA and protein (GSTO1-1 and GSTO2-2) products have been identified in multiple tissues (4). The omega-class GSTs are of considerable interest because of the discovery of their role in the reduction of methylated arsenic species and their genetic linkage to the age-at-onset of both Alzheimer's and Parkinson's diseases (5)(6)(7)(8)(9)). An omega-class GST has also been implicated in the processing and release of the proinflammatory cytokine interlukin-1 (10).…”

Metabolism and toxicity of arsenic in human urothelial cells expressing rat arsenic (+3 oxidation state)-methyltransferase

“…In rats and hamsters, DMAs is further methylated to yield trimethylarsine oxide (TMAs V O) (Yamauchi and Yamamura, 1985;Yoshida et al, 1998). Two classes of enzymes are involved in the methylation of iAs, including As V -reductases (Gregus and Nemeti, 2002;Radabaugh et al, 2002;Zakharyan and Aposhian, 1999;Zakharyan et al, 2001) and As III -methyltransferases Zakharyan et al, 1995). The metabolic conversion of iAs is generally recognized to be a determinant of the toxic and carcinogenic effects of this metalloid.…”