Functional polymorphism of human glutathione transferase A2.
OBJECTIVE
Single nucleotide polymorphisms that cause amino acid substitutions in enzymes involved in the metabolism of xenobiotics can potentially have a significant effect on the efficacy and safety of therapeutic drugs.


METHODS
We have utilized a bioinformatic approach to identify new polymorphisms in the glutathione transferase super family.


CONCLUSIONS
In this report we describe a P110S polymorphism in GSTA2 that occurs at a low frequency in Africans, Chinese and Europeans. The serine containing isoform has significantly diminished activity with a range of substrates including, delta-Androsten-3,17-dione, 1-chloro-2,4-dinitrobenzene and cumene hydroperoxide. The activity with cumene hydroperoxide may reflect a diminished physiological function since the glutathione peroxidase activity of GSTA2-2 plays a role in prostaglandin synthesis. In contrast, activity with p-nitrophenol acetate was significantly elevated. The position of this polymorphism in the active site and its effects on model substrates suggest that further investigation of its capacity to conjugate alkylating drugs is warranted.
Tetlow
Natasha
N
Molecular Genetics Group, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Board
Philip G
PG
D000349:Africa; D000735:Androstenedione / Q000378:metabolism*; D001555:Benzene Derivatives / Q000378:metabolism*; D001665:Binding Sites; D002681:China; D019295:Computational Biology; D004247:DNA / Q000097:blood / Q000235:genetics; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics*; D004137:Dinitrochlorobenzene / Q000378:metabolism*; D005060:Europe; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009596:Nitrophenols / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism
D001555:Benzene Derivatives; D004137:Dinitrochlorobenzene; D009596:Nitrophenols; D011994:Recombinant Proteins; D000735:Androstenedione; D004247:DNA; D005982:Glutathione Transferase; C007164:cumene hydroperoxide