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

doi:10.1006/geno.1999.5832

Genomics

Volume 58, Issue 3, 15 June 1999, Pages 263-269

https://doi.org/10.1006/geno.1999.5832 Get rights and content

Abstract

The gene for maleylacetoacetate isomerase (MAAI) (EC 5.2.1.2) was the last gene in the mammalian phenylalanine/tyrosine catabolic pathway to be cloned. We have isolated the human and murine genes and determined their genomic structure. The human gene spans a genomic region of ∼10 kb, has 9 exons ranging from 50 to 528 bp in size, and was mapped to 14q24.3–14q31.1 using fluorescence in situ hybridization. The complete catabolic pathway of phenylalanine/tyrosine is normally restricted to liver and kidney, but the maleylacetoacetate isomerase gene is expressed ubiquitously. This suggests a possible second role for the MAAI protein different from phenylalanine/tyrosine catabolism. We have searched for mutations in the maleylacetoacetate isomerase gene in four cases of unexplained severe liver failure in infancy with clinical similarities to hereditary tyrosinemia type I (pseudotyrosinemia). Several amino acid changes were identified, but all were found to retain MAAI activity and thus represent protein polymorphisms. We conclude that MAAI deficiency is not a common cause of the pseudotyrosinemic phenotype.

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Herein I summarize the physiological chemistry and pharmacology of the bifunctional enzyme glutathione transferase zeta 1 (GSTZ1)/ maleylacetoacetate isomerase (MAAI) relevant to human physiology, drug metabolism and disease. MAAI is integral to the catabolism of the amino acids phenylalanine and tyrosine. Genetic or pharmacological inhibition of MAAI can be pathological in animals. However, to date, no clinical disease consequences are unequivocally attributable to inborn errors of this enzyme. MAAI is identical to the zeta 1 family isoform of GST, which biotransforms the investigational drug dichloroacetate (DCA) to the endogenous compound glyoxylate. DCA is a mechanism-based inhibitor of GSTZ1 that significantly reduces its rate of metabolism and increases accumulation of potentially harmful tyrosine intermediates and of the heme precursor δ-aminolevulinic acid (δ-ALA). GSTZ1 is most abundant in rodent and human liver, with its concentration several fold higher in cytoplasm than in mitochondria. Its activity and protein expression are dependent on the age of the host and the intracellular level of chloride ions. Gene association studies have linked GSTZ1 or its protein product to various physiological traits and pathologies. Haplotype variations in GSTZ1 influence the rate of DCA metabolism, enabling a genotyping strategy to allow potentially safe, precision-based drug dosing in clinical trials.
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The tripeptide glutathione is presumed to be the most versatile nucleophile in biology. Based on its millimolar concentration and reversible thiol-disulfide conversion, glutathione is often referred to as the “cellular redox buffer.” However, this thermodynamic concept is misleading and glutathione exerts a plethora of physiological functions far beyond redox homeostasis. Most eukaryotes and many prokaryotes can use glutathione as a substrate or coenzyme for the enzymatic conversion of xenobiotics, disulfides, hydroperoxides, peroxynitrite, dehydroascorbic acid, Michael acceptors, nitrosothiols, aldehydes, and 2-oxoaldehydes. Glutathione is also involved in oxidative protein folding, tyrosine degradation, and iron sensing, as well as the biosynthesis of iron-sulfur clusters, deoxyribonucleotides, steroids, and eicosanoids. In this chapter, I will give an overview of the diverse roles of glutathione and glutathione-dependent enzymes not only for redox homeostasis and electrophile detoxification but also for anabolic and catabolic processes.
Regulation of dichloroacetate biotransformation in rat liver and extrahepatic tissues by GSTZ1 expression and chloride concentration
2018, Biochemical Pharmacology
Citation Excerpt :
The distribution of GSTZ1 is not confined to the liver. In 2002, Lantum et al. measured enzyme expression in several other organs and tissues harvested from 175 to 200 g male Fischer 344 rats [8], consistent with similar findings in humans [9,10]. The rat study [8] employed a polyclonal antibody to human GSTZ1 to examine protein expression through immunohistochemistry and immunoblot following immunoprecipitation, and reported enzyme activity toward maleylacetone and chlorofluoroacetic acid.
Biotransformation of dichloroacetate (DCA) to glyoxylate by hepatic glutathione transferase zeta 1 (GSTZ1) is considered the principal determinant of the rate of plasma clearance of the drug. However, several other organismal and subcellular factors are also known to influence DCA metabolism. We utilized a female rat model to study these poorly understood processes. Rats aged 4 weeks (young) and 42–52 weeks (adult) were used to model children and adults, respectively. Hepatic chloride concentrations, which influence the rate of GSTZ1 inactivation by DCA, were lower in rat than in human tissues and rats did not show the age dependence previously seen in humans. We found GSTZ1 expression and activity in rat brain, heart, and kidney cell-free homogenates that were age-dependent. GSTZ1 expression in brain was higher in young rats than adult rats, whereas cardiac and renal GSTZ1 expression levels were higher in adult than young rats. GSTZ1 activity with DCA could not be measured accurately in kidney cell-free homogenates due to rapid depletion of glutathione by γ-glutamyl transpeptidase. Following oral administration of DCA, 100 mg/kg, to rats, GSTZ1 expression and activity were reduced in all rat tissues, but chloride concentrations were not affected. Together, these data extend our understanding of factors that determine the in vivo kinetics of DCA.
Renal Xenobiotic Metabolism
2018, Comprehensive Toxicology: Third Edition
The kidney possess most of the common drug-metabolising enzymes, and thus is able to make an important contribution to the body’s metabolism of drugs and other xenobiotics. The catalytic activity of the various enzymes is lower than in the liver, however enzymes involved in the processing of GSH conjugates to their mercapturic acids primarily involves the kidney. Xenobiotic-metabolising enzymes are not evenly distributed along the nephron: cytochromes P450 and enzymes involved in conjugation, glucuronidation or sulfation are present in higher concentrations in proximal tubular cells then other regions. There are however exception where some isoenzymes of P450 and GST’s are selectively localized in cells of the thick ascending limb. Most of the major form of cytochrome P450 are detected in the kidneys of experimental animals and humans. However, members of the CYP1 family, CYP2D6 and CYP2E1 appear to be, absent in human kidney. GST’s have been most extensively characterised in rat and humans kidney. The renal enzyme cysteine conjugate β-lyase involved in the bioactivation of haloalkane and haloalkene S-conjugates have been cloned and sequenced from both rat and human kidney and shown to be identical to glutamine transaminase K and KAT. Cloning approaches have also demonstrated the presence in the kidney of multiple forms of UGT, flavin monooxygenases, CES and SULTS. Bioactivation of certain chemicals by SULTS can generate reactive metabolites that modify DNA and leads to renal cancer. All of the enzymes discussed in addition to detoxification of foreign chemicals, and in a few case causing bioactivation have endogenous functions in the body. Such as regulation of salt and water balance, the control of blood pressure and synthesis of vitamin D and there are many more physiological roles for these enzymes awaiting discovery.
Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1
2017, Pharmacology and Therapeutics
Citation Excerpt :
The GSTZ1 enzyme was first identified as a hepatic cytosolic enzyme (Board et al., 1997; Tong et al., 1998b), in common with most of the GSTs studied to date (Board & Menon, 2013). It was then shown that the GSTZ1 transcript is present in kidney, testis, heart, brain and other tissues of mice and humans (Fernandez-Canon et al., 1999). The GSTZ1 protein was shown to be expressed in these tissues in rats (Lantum et al., 2002a), albeit at lower levels in than in liver.
Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects.
GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate
2016, Biochimica et Biophysica Acta - General Subjects
Citation Excerpt :
Breast and liver cancer showed the most marked up- and downregulation of GSTZ1, respectively, and were chosen for further study. We also investigated GSTZ1 expression in the kidney because it is a known site of GSTZ1 expression [20,21,22] and the Oncomine data suggested possible downregulation of GSTZ1 in kidney cancer. In addition, due to its known role in drug metabolism, we hypothesized the non-tumor duodenum may express GSTZ1 and, therefore, also sought to study non-tumor and tumor duodenal tissue.
Dichloroacetate (DCA), commonly used to treat metabolic disorders, is under investigation as an anti-cancer therapy due to its ability to reverse the Warburg effect and induce apoptosis in tumor cells. While DCA's mechanism of action is well-studied, other factors that influence its potential as a cancer treatment have not been thoroughly investigated. Here we show that expression of glutathione transferase zeta 1 (GSTZ1), the enzyme responsible for conversion of DCA to its inactive metabolite, glyoxylate, is downregulated in liver cancer and upregulated in some breast cancers, leading to abnormal expression of the protein. The cellular concentration of chloride, an ion that influences the stability of GSTZ1 in the presence of DCA, was also found to be abnormal in tumors, with consistently higher concentrations in hepatocellular carcinoma than in surrounding non-tumor tissue. Finally, results from experiments employing two- and three-dimensional cultures of HepG2 cells, parental and transduced to express GSTZ1, demonstrate that high levels of GSTZ1 expression confers resistance to the effect of high concentrations of DCA on cell viability. These results may have important clinical implications in determining intratumoral metabolism of DCA and, consequently, appropriate oral dosing.

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^☆: The HGM-approved nomenclature for maleylacetoacetate isomerase gene is GSTZ1 (alias MAAI). Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession Nos. AF098311 to AF098318 and AF095582.

¹: To whom correspondence should be addressed. E-mail: [email protected].

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Regular ArticleGene Structure, Chromosomal Location, and Expression Pattern of Maleylacetoacetate Isomerase☆

Abstract

Anal. Biochem.

J. Biol. Chem.

Genomics

Biochem. Biophys. Res. Commun.

Methods Enzymol.

Cell

J. Biol. Chem.

J. Biol. Chem.

Methods Cell Biol.

Gapped BLAST and PSI-BLAST: a new generation of protein database search programs

Nucleic Acids Res.

Molecular characterization of Fdx1, a putidaredoxin-type (2Fe–2S) ferredoxin able to transfer electrons to the dioxin dioxygenase of Sphingomonas sp. RW1

Eur. J. Biochem.

Hereditary tyrosinemia and alpha-1-fetoprotein. I. Clinical value of alpha-fetoprotein in hereditary tyrosinemia

Pathol. Biol. (Paris)

Tyrosinemia type Ib caused by maleylacetoacetate isomerase deficiency: A new defect

Pediatr. Res.

Detoxication of base propenals and other alpha, beta-unsaturated aldehyde products of radical reactions and lipid peroxidation by human glutathione transferases

Proc. Natl. Acad. Sci. USA

Zeta, a novel class of glutathione transferase in a range of spices from plants to humans

Biochem. J.

Regular Article
Gene Structure, Chromosomal Location, and Expression Pattern of Maleylacetoacetate Isomerase☆