Gene Structure, Chromosomal Location, and Expression Pattern of Maleylacetoacetate Isomerase

Fernández-Cañón, José Manuel; Hejna, Jim; Reifsteck, Carol A.; Olson, Susan B.; Grompe, Markus

doi:10.1006/geno.1999.5832

Cited by 37 publications

(19 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in many microorganisms, such as A. nidulans, the MAAI gene is clustered with FAH and HGD (GenBank database). This strongly suggests that tyrosine degradation is actually the major role for the MAAI enzyme (11,13,18). Consistent with this, we have shown that MAAI knockout mice become ill when fed a "natural" diet.…”

Section: Discussionsupporting

confidence: 80%

“…MAAI activity was measured spectrophotometrically in the presence of excess amounts of HGD and FAH. The enzymatic assay was performed as previously reported with slight modifications (11,12,14).…”

Section: Methodsmentioning

confidence: 99%

“…Previously the MAAI gene and MAAI activity were tested in patients manifesting "pseudotyrosinemia." However, no individuals with MAAI mutations were found, although several cDNA polymorphisms were discovered (11). Therefore, it remains unclear whether MAAI deficiency actually exists in human patients and what the phenotype of human MAAI deficiency may be.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Fernández-Cañón¹,

Baetscher²,

Finegold

et al. 2002

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Fernández-Cañón¹,

Baetscher²,

Finegold

et al. 2002

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…GSTZ1 catalyzes the dehalogenation of dichloroacetate (DCA) to glyoxylate (Tong et al, 1998). As the penultimate enzyme of tyrosine/phenylalanine catabolism, GSTZ1 isomerizes maleylacetoacetate to fumarylacetoacetate (Fernández-Cañón et al, 1999). Studies with GSTZ1 knock-out mice showed that these mice survived unless challenged with a diet high in protein, tyrosine, or homogentisic acid (Fernán-dez-Cañón et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

Gu²,

James³

et al. 2011

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Glutathione transferase 1 (GSTZ1), also known as maleylacetoacetate isomerase, catalyzes the penultimate step of tyrosine catabolism and metabolizes several ␣-halocarboxylic acids, including dichloroacetic acid (DCA), an investigational drug used for lactic acidosis and, recently, solid tumors. Age-related differences have been suggested in DCA pharmacotoxicology, but no information is available on GSTZ1 ontogeny in humans. Here, we investigated the cytosolic GSTZ1 developmental expression pattern and the influence of haplotype on GSTZ1 activity with DCA by using human livers from donors between 10 weeks gestation and 74 years. GSTZ1 expression was very low in fetal livers (<2 pmol of GSTZ1/mg cytosol). The expression began to increase after birth in an age-dependent manner until age 7 years. GSTZ1 was then sustained at stable, yet variable, levels (median, 20.0 pmol/mg cytosol; range, 4.8-47.3 pmol/mg cytosol) until age 74 years. GSTZ1 activity with DCA was strongly associated with haplotype and expression level. Samples homozygous or heterozygous for GSTZ1A exhibited ϳ3-fold higher DCA dechlorinating activity than samples carrying other alleles at a given level of expression. The correlations (r 2 ) between activity and expression were 0.90 and 0.68, respectively, for GSTZ1A carriers (n ‫؍‬ 11) and noncarriers (n ‫؍‬ 61). GSTZ1 is expressed in mitochondria in addition to cytosol. The GSTZ1A allele exhibited similar effects in the mitochondrial fraction by conferring a higher activity with DCA. In summary, we report a neonatal onset and an age-related increase in GSTZ1 protein expression during human liver development. Haplotype influenced GSTZ1 activity with DCA but not protein expression.

show abstract

“…The multiorgan toxicity of DCA also indicates that GSTZ1-1 may be expressed in different organs. Northern blot analyses of mouse and human tissue samples show that GSTZ1-1 is expressed in multiple tissues (Board et al, 1997;Fernández-Cañón et al, 1999). Protein expression and activities of GSTZ1-1 in rat tissues have not been determined.…”

mentioning

confidence: 99%

Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

Lantum

Baggs²,

Krenitsky³

et al. 2002

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Glutathione transferase zeta (GSTZ1-1) catalyzes the biotransformation of a range of ␣-haloacids, including dichloroacetic acid (DCA), and the penultimate step in the tyrosine degradation pathway. DCA is a rodent carcinogen and a common drinking water contaminant. DCA also causes multiorgan toxicity in rodents and dogs. The objective of this study was to determine the expression and activities of GSTZ1-1 in rat tissues with maleylacetone and chlorofluoroacetic acid as substrates. GSTZ1-1 protein was detected in most tissues by immunoblot analysis after immunoprecipitation of GSTZ1-1 and by immunohistochemical analysis; intense staining was observed in the liver, testis, and prostate; moderate staining was observed in the brain, heart, pancreatic islets, adrenal medulla, and the epithelial lining of the gastrointestinal tract, airways, and bladder; and sparse staining was observed in the renal juxtaglomerular regions, skeletal muscle, and peripheral nerve tissue. These patterns of expression corresponded to GSTZ1-1 activities in the different tissues with maleylacetone and chlorofluoroacetic acid as substrates. Specific activities ranged from 258 ؎ 17 (liver) to 1.1 ؎ 0.4 (muscle) nmol/min/mg of protein with maleylacetone as substrate and from 4.6 ؎ 0.89 (liver) to 0.09 ؎ 0.01 (kidney) nmol/min/mg of protein with chlorofluoroacetic acid as substrate. Rats given DCA had reduced amounts of immunoreactive GSTZ1-1 protein and activities of GSTZ1-1 in most tissues, especially in the liver. These findings indicate that the DCA-induced inactivation of GSTZ1-1 in different tissues may result in multiorgan disorders that may be associated with perturbed tyrosine metabolism.Glutathione transferases (GST 1 ) are a multigene family of phase II drug-metabolizing enzymes that catalyze the conjugation of glutathione with a range of endogenous and exogenous substrates (Armstrong, 1997;Salinas and Wong, 1999). Soluble and membrane-bound GSTs are expressed in many tissues, and soluble GSTs constitute 1 to 5% of total cytosolic protein (Morgenstern et al., 1984;Sundberg et al., 1993;Rowe et al., 1997). Activities with model substrates and the subcellular localization of GSTA, GSTM, GSTP, GSTT, and GSTO class GSTs and of microsomal GST1 have been previously characterized (Meyer et al., 1991;Hiratsuka et al., 1994;Mannervik and Widersten, 1995;Armstrong, 1997;Otieno et al., 1997;Yin et al., 2001).The expression of GSTs is regulated pre-and post-translationally in a tissue-specific manner resulting in protein products that differ quantitatively in different tissues (Tu et al., 1983;Rozell et al., 1993;Rowe et al., 1997). Testes express the highest amount of total GST protein per milligram cytosolic protein followed by the liver, brain, pancreas, adrenals, heart, and lung (DePierre and Morgenstern, 1983;Listowsky et al., 1998). Major GST-expressing tissues are the principal sites for drug and chemical metabolism indicative of the role of GSTs in the biotransformation of xenobiotics (Pabst et al., 1973;Armstrong, 1997). Studies...

show abstract

Gene Structure, Chromosomal Location, and Expression Pattern of Maleylacetoacetate Isomerase

Cited by 37 publications

References 23 publications

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

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

Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

Contact Info

Product

Resources

About