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GSTZ1
GSTZ1 Full Name
glutathione S-transferase zeta 1
GSTZ1 Introduction
GSTZ1 encodes a bifunctional enzyme that belongs to the zeta class of the glutathione S-transferase superfamily and is also known as maleylacetoacetate isomerase (MAAI). The enzyme occupies a unique position at the intersection of amino acid catabolism and xenobiotic metabolism, functioning as both a GST and a critical isomerase in the tyrosine and phenylalanine degradation pathway. In its MAAI capacity, GSTZ1 catalyzes the glutathione-dependent isomerization of maleylacetoacetate to fumarylacetoacetate, an essential step in the catabolism of tyrosine that ultimately yields the Krebs cycle intermediates fumarate and acetoacetate. This pathway operates exclusively in hepatocytes and proximal renal tubular cells, the only cell types expressing the complete tyrosine degradation enzyme cascade. In its GST capacity, GSTZ1 catalyzes the biotransformation of the environmental contaminant and investigational drug dichloroacetic acid (DCA) to glyoxylate, a reaction with important pharmacological implications. Notably, DCA functions as a mechanism-based inhibitor of GSTZ1, progressively inactivating the enzyme upon prolonged exposure and leading to accumulation of potentially harmful tyrosine catabolic intermediates.
Genetic polymorphisms in GSTZ1 give rise to five known haplotypic variants that differ significantly in their catalytic efficiency toward both DCA and maleylacetoacetate, influencing the rate of DCA clearance and the degree of intermediate metabolite accumulation. These haplotype-dependent differences have direct implications for DCA-based therapeutic strategies, as they determine drug pharmacokinetics and toxicity profiles, supporting a pharmacogenomic approach to dosing. Biallelic loss-of-function mutations in GSTZ1 cause maleylacetoacetate isomerase deficiency (MAAID), a typically benign condition characterized by mild elevations in succinylacetone in blood and urine, usually identified incidentally through newborn screening. Gene association studies have linked GSTZ1 variants to diverse pathological traits, including longevity, bipolar disorder, and cancer — where GSTZ1 deficiency has been connected to tumor metabolism through Keap1 modification and altered redox signaling. In animal models, complete GSTZ1 ablation activates oxidative stress response pathways and causes phenylalanine-induced leukopenia, suggesting broader physiological roles that extend beyond tyrosine catabolism to include antioxidant defense and immune regulation.
Figure 1. GSTZ1 knockout promotes HCC tumorigenesis in vivo via activation of IGF1R-mediated antiapoptotic pathway. (Source: Yang F, et al. 2019)
Alternate Names for GSTZ1
GSTZ1; glutathione S-transferase zeta 1; MAI; MAAI; GSTZ1-1; maleylacetoacetate isomerase; maleylacetone isomerase; glutathione S-aryltransferase; glutathione S-alkyltransferase; glutathione transferase zeta 1; glutathione S-aralkyltransferase; S-(hydroxyalkyl)glutathione lyase;
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