Identification, Characterization, and Crystal Structure of the Omega Class Glutathione Transferases

Abstract

A new class of glutathione transferases has been discovered by analysis of the expressed sequence tag data base and sequence alignment. Glutathione S-transferases (GSTs) of the new class, named Omega, exist in several mammalian species and Caenorhabditis elegans. In humans, GSTO 1-1 is expressed in most tissues and exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities characteristic of the glutaredoxins. The structure of GSTO 1-1 has been determined at 2.0-Å resolution and has a characteristic GST fold (Protein Data Bank entry code 1eem). The Omega class GSTs exhibit an unusual N-terminal extension that abuts the C terminus to form a novel structural unit. Unlike other mammalian GSTs, GSTO 1-1 appears to have an active site cysteine that can form a disulfide bond with glutathione.

Glutathione S-transferase polymorphisms: cancer incidence and therapy

“…Among the Australian, African and Chinese populations, GSTO1*A was the most prevalent haplotype with a frequency ranging from 0.6 to 0.9; whereas GSTO1*B*A was the least common, with a frequency of 0.01-0.05 (Whitbread et al, 2003). 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).…”

“…First, X-ray crystallography shows a unique 19-residue N-terminus extension that forms a structural unit quite unlike any found in other classes. At present, its function remains undefined (Board et al, 2000). Second, known substrates of other GSTs are not catalysed by GSTO.…”

“…GSTO1 is a single gene located on chromosome 10 that codes for proteins expressed abundantly in the liver, macrophages, glial and endocrine cells (Board et al, Table 2) (Board et al, 2000). Among the Australian, African and Chinese populations, GSTO1*A was the most prevalent haplotype with a frequency ranging from 0.6 to 0.9; whereas GSTO1*B*A was the least common, with a frequency of 0.01-0.05 (Whitbread et al, 2003).…”

“…The isozyme GSTZ1*A has the highest catalytic activity toward dichloroacetic acid, an investigational drug for certain metabolic disorders and a nephrotoxic metabolite of industrial solvents (Board et al, 2000;Guo et al, 2005). In contrast, GSTZ1*D (p.T82M) has a reduced catalytic activity and has been associated with inborn errors in tyrosine metabolism, although the disorders have also been attributed to mutations in other enzymes.…”

Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

“…GSTO1 (glutathione transferase omega 1) is a member of the glutathione S-transferase (GST) family of phase II enzymes that catalyze glutathione-dependent detoxification. 32 The role of GST has been evaluated in drug resistance. Schisselbauer et al 33 reported that an elevated GST level in tumors was detected after the development of clinical drug resistance.…”