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Molecular and Cellular Biology, July 2002, p. 4943-4951, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4943-4951.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Maleylacetoacetate Isomerase (MAAI/GSTZ)-Deficient Mice Reveal a Glutathione-Dependent Nonenzymatic Bypass in Tyrosine Catabolism

José Manuel Fernández-Cañón,^1* Manfred W. Baetscher,¹ Milton Finegold,² Terry Burlingame,¹ K. Michael Gibson,¹ and Markus Grompe^1,3

Department of Molecular and Medical Genetics,¹ Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon,³ Department of Pathology, Texas Children's Hospital, Houston, Texas²

Received 29 November 2001/ Returned for modification 18 March 2002/ Accepted 26 March 2002

In mammals, the catabolic pathway of phenylalanine and tyrosine is found in liver (hepatocytes) and kidney (proximal tubular cells). There are well-described human diseases associated with deficiencies of all enzymes in this pathway except for maleylacetoacetate isomerase (MAAI), which converts maleylacetoacetate (MAA) to fumarylacetoacetate (FAA). MAAI is also known as glutathione transferase zeta (GSTZ1). Here, we describe the phenotype of mice with a targeted deletion of the MAAI (GSTZ1) gene. MAAI-deficient mice accumulated FAA and succinylacetone in urine but appeared otherwise healthy. This observation suggested that either accumulating MAA is not toxic or an alternate pathway for MAA metabolism exists. A complete redundancy of MAAI could be ruled out because substrate overload of the tyrosine catabolic pathway (administration of homogentisic acid, phenylalanine, or tyrosine) resulted in renal and hepatic damage. However, evidence for a partial bypass of MAAI activity was also found. Mice doubly mutant for MAAI and fumarylacetoacetate hydrolase (FAH) died rapidly on a normal diet, indicating that MAA could be isomerized to FAA in the absence of MAAI. Double mutants showed predominant renal injury, indicating that this organ is the primary target for the accumulated compound(s) resulting from MAAI deficiency. A glutathione-mediated isomerization of MAA to FAA independent of MAAI enzyme was demonstrated in vitro. This nonenzymatic bypass is likely responsible for the lack of a phenotype in nonstressed MAAI mutant mice.

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* Corresponding author. Present address: Departamento de Bioquimica y Biología Molecular, Facultad de Veterinaria, Campus de Vegazana, Universidad de Leon, 24007 Leon, Spain. Phone: 34 987 291226. Fax: 34 987 291226. E-mail: dbbfjc{at}unileon.es.

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Molecular and Cellular Biology, July 2002, p. 4943-4951, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4943-4951.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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