Functional polymorphism of human glutathione transferase A2

Area of Science:

• Pharmacogenomics
• Enzyme kinetics
• Molecular biology

Background:

• Genetic variations, specifically single nucleotide polymorphisms (SNPs), can alter enzyme function.
• Enzymes metabolizing xenobiotics are crucial for drug efficacy and safety.
• The glutathione transferase (GST) superfamily plays a key role in detoxification.

Purpose of the Study:

• To identify novel polymorphisms within the glutathione transferase superfamily using a bioinformatic approach.
• To characterize the functional impact of a newly identified polymorphism in GSTA2.

Main Methods:

• Bioinformatic analysis to screen for polymorphisms in GSTs.
• Enzyme activity assays using various substrates to assess the function of the polymorphic variant.
• Analysis of polymorphism frequency across different ethnic populations.

Main Results:

• A P110S polymorphism in GSTA2 was identified, occurring at low frequencies in African, Chinese, and European populations.
• The serine-containing GSTA2 isoform exhibited significantly reduced activity with substrates like delta-Androsten-3,17-dione, 1-chloro-2,4-dinitrobenzene, and cumene hydroperoxide.
• Activity with p-nitrophenol acetate was significantly increased.
• The diminished activity with cumene hydroperoxide may impair the enzyme's physiological role in prostaglandin synthesis.

Conclusions:

• The P110S polymorphism in GSTA2 results in a catalytically altered enzyme.
• This altered enzyme activity, particularly the reduced conjugation of xenobiotics, may have implications for drug response.
• Further research is recommended to evaluate the role of this polymorphism in the metabolism of alkylating drugs.