DCA is primarily biotransformed to glyoxylate by the bifunctional enzyme glutathione transferase zetal and maleylacetoacetate isomerase (GSTzl/ MAAI), which also catalyzes the penultimate step in the phenylalanine and tyrosine catabolic pathway.
KEY WORDS: cancer, dichloroacetate, glutathione transferase zeta, hereditary tyrosinemia, maleylacetoacetate isomerase, mitochondrial disease, peripheral neuropathy, pyruvate dehydrogenase, toxicogenetics.
DCA is dehalogenated to glyoxylate by the cytosolic zeta-1 family isoform of glutathione transferase (GSTzl), which is identical to maleylacetoacetate isomerase (MAAI), the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway [see Supplemental Material, Figure 2 (doi:10.
Genetic or DCA-induced ablation of GSTzl/MAAI causes accumulation of the MAAI substrates maleylacetone and, presumably, maleylacetoacetate (MAA) (Ammini et al.
Fernandez-Canon and Penalva (1998) have reported the Zeta GSTs in Aspergillus nidulans and humans are identical to an enzyme maleylacetoacetate isomerase (MAAI), which catalyzes the glutathione-dependent cis--trans isomerization of maleylacetoacetate to fumarylacetoacetate in the catabolic pathway of tyrosine/phenylalanine.
The first three-dimensional structure of a Zeta class GST has been characterized from Arabidopsis, which differs catalytically from previously characterised GSTs in that it adds glutathione reversibly to the cis double bond of maleylacetoacetate, allowing bond rotation before elimination of glutathione to yield fumarylacetoacetate, as those with Aspergillus nidulans and human (Thom et al.
Characterization of a fungal maleylacetoacetate isomerase gene and identification of its human homologue.
Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism.