Clinical physiology and pharmacology of GSTZ1/MAAI

Herein I summarize the physiological chemistry and pharmacology of the bifunctional enzyme glutathione transferase zeta 1 (GSTZ1)/ maleylacetoacetate isomerase (MAAI) relevant to human physiology, drug metabolism and disease. MAAI is integral to the catabolism of the amino acids phenylalanine and tyrosine. Genetic or pharmacological inhibition of MAAI can be pathological in animals. However, to date, no clinical disease consequences are unequivocally attributable to inborn errors of this enzyme. MAAI is identical to the zeta 1 family isoform of GST, which biotransforms the investigational drug dichloroacetate (DCA) to the endogenous compound glyoxylate. DCA is a mechanism-based inhibitor of GSTZ1 that significantly reduces its rate of metabolism and increases accumulation of potentially harmful tyrosine intermediates and of the heme precursor δ-aminolevulinic acid (δ-ALA). GSTZ1 is most abundant in rodent and human liver, with its concentration several fold higher in cytoplasm than in mitochondria. Its activity and protein expression are dependent on the age of the host and the intracellular level of chloride ions. Gene association studies have linked GSTZ1 or its protein product to various physiological traits and pathologies. Haplotype variations in GSTZ1 influence the rate of DCA metabolism, enabling a genotyping strategy to allow potentially safe, precision-based drug dosing in clinical trials.