causes renal tubular dysfunction in a Fanconi-like syndrome of renal failure and vitamin D-resistant rickets (Jacobs, van Beurden, Klomp, Berger, & van den Berg, 2006).
This results in accumulation of toxic metabolites; maleylacetoacetate
, fumarylacetoacetate, succinyl acetoacetate and succinylacetone, causing progressive hepatic and renal damage in untreated patients1 Long-term complications of untreated HT-I is hepatic cirrhosis and hepatocellular carcinoma.
In contrast, it has been known that FAH deficiency may cause accumulation of maleylacetoacetate
(MAA) and fumarylacetoacetate (FAA) and their derivatives, such as succinylacetoacetic acid (SAA) and succinylacetone (SA), and these may cause the hepatorenal features.
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.
Crystal Structure of Maleylacetoacetate
Isomerase/ Glutathione Transferase Zeta Reveals the Molecular Basis for Its Remarkable Catalytic Promiscuity.
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.
Intermediary metabolism and catabolism enzymes 2D3 6e-17 AY431429 Carboxypeptidase A Mosquito 1C1 2e-26 NP_918077 Putative carboxyme- thylenebmenolidase Rice 1F4 1e-38 XP_316948 Nudix * Mosquito 1F10 1e-76 CAE70680 Isocitrate dehydro- genase * Nematode 1H6 3e-27 XP_308198 Pancreatic lipase * Mosquito 15C3 2e-20 CAA93088 Giutathione S-trans- ferase * Nematode 15G3 9e-11 EAL31332 Maleylacetoacetate
isomerase * Fly AVII.
GSTZ1d: a new allele of glutathione transferase zeta and maleylacetoacetate
2004) reported that pretreatment with either DCA or TCE inhibits the cytosolic enzyme glutathione S-transferase (GST) [xi], also known as maleylacetoacetate
(MAA) isomerase, and TCA pretreatment does not.