Crystal structure of maleylacetoacetate
isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity.
Toxic metabolites and their derivates such as fumarylacetoacetate (FAA), maleylacetoacetate
, succynylacetoacetate (SA) and SA playa major role in tissue damage with hepatic, renal and neurological findings (2).
FAH deficiency leads to an accumulation of fumarylacetoacetate, maleylacetoacetate
, succinylacetoacetone, and succinylacetone.
A few enzymes of the GST family, including PcpC, maleylacetoacetate
isomerase, and maleylpyruvate isomerase, have complex and unusual mechanisms involving additional steps before and/or after the nucleophilic attack of glutathione on an electrophilic intermediate [32-36].
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.2
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.
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.
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.
Toxic metabolites and their derivates such as FAA, maleylacetoacetate
, succinyl acetoacetate and succinyl acetone (SA) play a major role in tissue damage with hepatic, renal and neurological findings.
GSTZ1d: a new allele of glutathione transferase zeta and maleylacetoacetate