Characterization of the human Omega class glutathione transferase genes and associated polymorphisms

Abstract

The Omega class glutathione transferases (GSTs) have been identified in many organisms, including human, mouse, rat, pig, Caenorhabditis eglands and Drosophila melanogaster. These GSTs have poor activity with common GST substrates, but exhibit novel glutathione-dependent thioltransferase, dehydroascorbate reductase and monomethylarsonate reductase activities, and modulate Ca release by ryanodine receptors. An investigation of the genomic organization of human GSTO1 identified a second actively transcribed member of the Omega class (GSTO1). Both GSTO1 and GSTO2 are composed of six exons and are separated by 7.5 kb on chromosome 10q24.3. A third sequence that appears to be a reverse-transcribed pseudogene (GSTO3p) has been identified on chromosome 3. GSTO2 has 64% amino acid identity with GSTO1 and conserves the cysteine residue at position 32, which is thought to be important in the active site of GSTO1. Expression of GSTO2 mRNA was seen in a range of tissues, including the liver, kidney, skeletal muscle and prostate. The strongest GSTO2 expression was in the testis, which also expresses a larger transcript than other tissues. Characterization of recombinant GSTO2 has been limited by its poor solubility. Two functional polymorphisms of GSTO1 have been identified. One alters a splice junction and causes the deletion of E155 and another results in an A140D substitution. Characterization of these variants revealed that the A140D substitution affects neither heat stability, nor activity towards 1-chloro-2,4-dinitrobenzene or hydroxyethyl disulphide. In contrast, deletion of residue E155 appears to contribute towards both a loss of heat stability and increased enzymatic activity.

Glutathione S-transferase mu, omega, pi, and theta class variants and smoking in Parkinson's disease

“…Fischer's Exact Test was used to test for linkage disequilibrium between GSTO1 and GSTO2. The two polymorphisms are located only 7.5 kb apart on chromosome 10q24.3 [30] and in our association analyses we consistently estimated very similar effect sizes for both SNPs.…”

“…Fischer's Exact Test was used to test for linkage disequilibrium between GSTO1 and GSTO2. The two polymorphisms are located only 7.5 kb apart on chromosome 10q24.3 [30] and in our association analyses we consistently estimated very similar effect sizes for both SNPs.All calculations were performed on the entire PEG population and Caucasian subjects only (n=235 cases, 220 controls), to address the potential for population stratification. We used Mendel 6.01 software to perform linkage disequilibrium analysis, and used SAS 8.0 software to perform all other analyses.…”

“…All GST polymorphisms were genotyped via pyrosequencing using established methods [2,16,30]. SNPs and their NCBI SNP reference numbers are noted in Table 1, and further information including primer sequences and fragment lengths are available upon request.…”

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).…”

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

“…The recently identified omega-class glutathione transferases (GSTs) are widely distributed across a range of species from Caenorhabditis elegans to humans (2,3). 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)).…”