GSTZ1d: a new allele of glutathione transferase zeta and maleylacetoacetate isomerase

The zeta class glutathione transferases (GSTs) are known to catalyse the is omerization of maleylacetoacetate (MAA) to fumarylacetoacetate (FAA), and t he biotransformation of dichloroacetic acid to glyoxylate. A new allele of human GSTZ1, characterized by a Thr82Met substitution and termed GSTZ1d, ha s been identified by analysis of the expressed sequence tag (EST) database. In European Australians, GSTZ1d occurs with a frequency of 0.16. Like GSTZ 1b-1b and GSTZ1c-1c, the new isoform has low activity with dichloroacetic a cid compared with GSTZ1a-1a. The low activity appears to be due to a high s ensitivity to substrate inhibition. The maleylacetoacetate isomerase (MAAI) activity of all known variants was compared using maleylacetone as a subst rate. Significant differences in activity were noted, with GSTZ1a-1a having a notably lower catalytic efficiency. The unusual catalytic properties of GSTZ1a-1a in both reactions suggest that its characteristic arginine at pos ition 42 plays a significant role in the regulation of substrate access and /or product release. The different amino acid substitutions have been mappe d on to the recently determined crystal structure of GSTZ1-1 to evaluate an d explain their influence on function. Pharmacogenetics 11:671-678 (C) 2001 Lippincott Williams & Wilkins.