Synthesis of model compounds for maleylacetoacetic acid. Maleylacetone

Fowler, Joanna S.; Seltzer, Stanley

doi:10.1021/jo00835a075

Cited by 40 publications

(30 citation statements)

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“…The isomerase activities in homogenates of the different tissues were determined by measuring the rate of formation of FA from MA (Fowler and Seltzer, 1970). Reaction mixtures contained protein (10 -80 g), MA (1 mM), and glutathione (1 mM) in a final volume of 0.5 ml of 0.01 M potassium phosphate buffer (pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

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

Lantum

Baggs²,

Krenitsky³

et al. 2002

Drug Metab Dispos

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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...

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Section: Methodsmentioning

confidence: 99%

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

Lantum

Baggs²,

Krenitsky³

et al. 2002

Drug Metab Dispos

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“…As GSH-Sepharose column materials are now available commercially, enzyme isolation should be greatly facilitated. The substrate, maleylacetone (45a) has been synthesized chemically (150) [there is also a semienzymatic synthesis from homogentisic acid (151) reported]. It can be stored at -6°C for several weeks but, in aqueous solution or chloroform, isomerization to fumarylacetone is rapid (150).…”

Section: Maleyl Lsomerasesmentioning

confidence: 99%

“…The substrate, maleylacetone (45a) has been synthesized chemically (150) [there is also a semienzymatic synthesis from homogentisic acid (151) reported]. It can be stored at -6°C for several weeks but, in aqueous solution or chloroform, isomerization to fumarylacetone is rapid (150). In water, maleylacetone exists exclusively as the "pseudoacid" (47).…”

Section: Maleyl Lsomerasesmentioning

confidence: 99%

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Mechanism of Action of Glutathione‐Dependent Enzymes

Douglas

1987

Advances in Enzymology - And Related Areas of Molecular Biology

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“…In contrast to maleylacetate which, depending on the pH, exists as the keto and the lactol forms, different solution structures have been reported for maleylacetone, methylmaleylacetone, and acetopyruvate, including an enol tautomer, which under physiological conditions accounts for approximately 50% of the solution structure mixture (3,12,22,29). The only apparent difference between maleylacetate and (methyl) maleylacetone is the higher acidity of the methylene protons in the latter case, favoring formation of the enol tautomer.…”

mentioning

confidence: 99%

Monitoring Key Reactions in Degradation of Chloroaromatics by In Situ ¹ H Nuclear Magnetic Resonance: Solution Structures of Metabolites Formed from cis -Dienelactone

et al. 2002

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A 1 H nuclear magnetic resonance ( 1 H NMR) assay was used to study the enzymatic transformation of cis-dienelactone, a central intermediate in the degradation of chloroaromatics. It was shown that the product of the cis-dienelactone hydrolase reaction is maleylacetate, in which there is no evidence for the formation of 3-hydroxymuconate. Under acidic conditions, the product structure was 4-carboxymethyl-4-hydroxybut-2-en-4-olide. Maleylacetate was transformed by maleylacetate reductase into 3-oxoadipate, a reaction competing with spontaneous decarboxylation into cis-acetylacrylate. One-dimensional 1 H NMR in 1 H 2 O could thus be shown to be an excellent noninvasive tool for monitoring enzyme activities and assessing the solution structure of substrates and products.A major route for mineralization of chloroaromatic compounds by microorganisms is their transformation into chlorocatechols and their further metabolism by enzymes of the chlorocatechol pathway (24). In this metabolic pathway, chlorocatechols are subject to intradiol cleavage to form the respective chloromuconates, which are converted by chloromuconate cycloisomerases into cis-or trans-dienelactone. The dienelactones undergo hydrolysis by dienelactone hydrolase. The hydrolysis product formed during the metabolism of 4-chlorocatechol was tentatively identified as "maleylacetate" based on its absorption characteristics ( max ϭ 243 nm in aqueous alkali) by Evans et al. (11). Similarly, Tiedje et al. (31) postulated maleylacetate and chloromaleylacetate as products formed during the metabolism of 4-chloro-and 3,5-dichlorocatechol, respectively. Those authors noted, however, that UV absorption was essentially quenched upon acidification, a behavior resembling keto-enol tautomerism, raising the question of the actual solution structure of maleylacetate. More recently, Seibert et al. claimed that the enol form (3-hydroxy-2,4-hexadienedioate, 3-hydroxymuconate) is thermodynamically favored under physiological conditions and exhibits an absorption maximum at 243 nm (28). The disappearance of this absorption under acidic conditions was believed to be due to the presence of the keto form, 3-oxo-cis-4-hexenedioate (maleylacetate in the strict sense), under these conditions. Despite the authors' assumption that 3-hydroxymuconate was the actual substrate of the purified reductase, the enzyme was termed "maleylacetate" reductase. Later, Prucha et al. (23) showed that the hydrolysis product of 3-methyldienelactone, supposedly 3-methylmaleylacetate or 3-hydroxy-4-methylmuconate, has a cyclic structure under acidic conditions (4-carboxymethylene-4-hydroxy-3-methylbut-2-en-4-olide, 4-hydroxy-3-methylmuconolactone), while no indication of the configuration under physiological conditions was given. Thus, although the structure of the decarboxylation product has been published (27), the actual solution structure of "maleylacetate" remained uncertain, presumably due to its reportedly high instability."Maleylacetate" is an intermediate not only in the degradation of chlo...

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Synthesis of model compounds for maleylacetoacetic acid. Maleylacetone

Abstract: tion of the pregnajervanes and for his valued counsel during the course of this work. The preparation of large quantities of intermediates was capably carried out by Mr. R. Salzmann.

Cited by 40 publications

References 0 publications

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

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

Mechanism of Action of Glutathione‐Dependent Enzymes

Monitoring Key Reactions in Degradation of Chloroaromatics by In Situ ¹ H Nuclear Magnetic Resonance: Solution Structures of Metabolites Formed from cis -Dienelactone

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Synthesis of model compounds for maleylacetoacetic acid. Maleylacetone

Abstract: tion of the pregnajervanes and for his valued counsel during the course of this work. The preparation of large quantities of intermediates was capably carried out by Mr. R. Salzmann.

Cited by 40 publications

References 0 publications

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

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

Mechanism of Action of Glutathione‐Dependent Enzymes

Monitoring Key Reactions in Degradation of Chloroaromatics by In Situ 1 H Nuclear Magnetic Resonance: Solution Structures of Metabolites Formed from cis -Dienelactone

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Monitoring Key Reactions in Degradation of Chloroaromatics by In Situ ¹ H Nuclear Magnetic Resonance: Solution Structures of Metabolites Formed from cis -Dienelactone