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Structure of human glutathione S-transferase class Mu genes.

ABSTRACT: Nucleotide sequencing of a human cosmid clone shows that the exon-intron structures of a glutathione S-transferase multigene family are conserved between man and rat, that the human gene family is clustered and that gene conversion events have occurred within the cluster. In addition, between man and rat, there is a high degree of nucleotide sequence identity not only in exons but also in some introns. These conserved sequences are coincident with homologous sequences subject to gene conversion in both species, and hence the utilization of gene conversion by this gene family has itself been conserved. By using transient-expression assay the conserved/converted regions are shown to be capable of modulating transcriptional activity. The data suggest that DNA repair by gene conversion may be a chemical immunity mechanism. which could result in acquired resistance to toxins and, in particular, drug resistance due to glutathione S-transferase in tumours.

SUBMITTER: Taylor JB

PROVIDER: S-EPMC1150179 | biostudies-other | 1991 Mar

REPOSITORIES: biostudies-other

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Cytosolic glutathione transferases from rat liver. Primary structure of class alpha glutathione transferase 8-8 and characterization of low-abundance class Mu glutathione transferases.

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Comprehensive analysis of the catalytic and structural properties of a mu-class glutathione s-transferase from Fasciola gigantica.

Project description:Glutathione S?transferases (GSTs) play an important role in the detoxification of xenobiotics. They catalyze the nucleophilic addition of glutathione (GSH) to nonpolar compounds, rendering the products water-soluble. In the present study, we investigated the catalytic and structural properties of a mu-class GST from Fasciola gigantica (FgGST1). The purified recombinant FgGST1 formed a homodimer composed of 25?kDa subunit. Kinetic analysis revealed that FgGST1 displays broad substrate specificity and shows high GSH conjugation activity toward 1-chloro-2,4-dinitrobenzene, 4-nitroquinoline-1-oxide, and trans-4-phenyl-3-butene-2-one and peroxidase activity towards trans-2-nonenal and hexa-2,4-dienal. The FgGST1 was highly sensitive to inhibition by cibacron blue. The cofactor (GSH) and inhibitor (cibacron blue) were docked, and binding sites were identified. The molecular dynamics studies and principal component analysis indicated the stability of the systems and the collective motions, respectively. Unfolding studies suggest that FgGST1 is a highly cooperative molecule because, during GdnHCl-induced denaturation, a simultaneous unfolding of the protein without stabilization of any partially folded intermediate is observed. The protein is stabilized with a conformational free energy of about 10?±?0.3?kcal?mol-1. Additionally, the presence of conserved Pro-53 and structural motifs such as N-capping box and hydrophobic staple, further aided in the stability and proper folding of FgGST1.

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