{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Glutathione S‐transferase zeta 1 (GSTZ1), also known as maleylacetoacetate isomerase (MAAI), is a bifunctional enzyme that plays a central role in both endogenous metabolism and xenobiotic biotransformation. In its canonical function, GSTZ1 catalyzes the isomerization of maleylacetoacetate to fumarylacetoacetate in the phenylalanine/tyrosine catabolic pathway, thereby preventing the accumulation of toxic intermediates and mitigating oxidative stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Structural studies reveal that naturally occurring polymorphisms can markedly affect catalytic efficiency and substrate handling, with specific allelic variants showing unique kinetics toward substrates such as dichloroacetate (DCA)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In the context of xenobiotic metabolism, GSTZ1 is responsible for the dechlorination of DCA, and genetic variability in GSTZ1 has been linked to alterations in drug kinetics and toxicity, influencing both adult and pediatric pharmacogenetic profiles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, loss or downregulation of GSTZ1 leads to glutathione depletion, accumulation of reactive intermediates, and consequent activation of the NRF2-dependent antioxidant response, which has been implicated in hepatocellular carcinoma progression by promoting aerobic glycolysis and enhancing proliferative signaling such as via the IGF1 receptor."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Beyond its roles in liver metabolism and cancer, GSTZ1 expression is also induced during adipocyte differentiation, suggesting that it contributes to broader aspects of cellular metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, recent advances using genetic engineering have enabled the conversion of GSTZ1 into a selenoenzyme with enhanced glutathione peroxidase activity, a modification that underscores its potential utility as a therapeutic antioxidant tool."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these studies highlight GSTZ1’s pivotal role in maintaining metabolic homeostasis, regulating cellular redox balance, and modulating responses to chemical exposure, with significant implications for cancer biology, pharmacogenetics, and metabolic disease.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anneke C Blackburn, Klaus I Matthaei, Cindy Lim, et al. 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