Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetrachlorohydroquinone dehalogenase catalyzes the reductive dehalogenation of tetrachlorohydroquinone and trichlorohydroquinone during the biodegradation of the xenobiotic compound pentachlorophenol by Sphingobium chlorophenolicum. The mechanism of this transformation is of interest because it is unusual and difficult, and because aerobic microorganisms rarely catalyze reductive dehalogenation reactions. Tetrachlorohydroquinone dehalogenase is a member of the glutathione S-transferase superfamily. Many enzymes in this superfamily are capable of catalyzing nucleophilic aromatic substitution reactions. On the basis of this precedent, we have considered a mechanism for tetrachlorohydroquinone dehalogenase that involves a nucleophilic aromatic substitution reaction, either via an S(N)Ar mechanism or an S(RN)1-like mechanism, in the initial part of the reaction. Mechanistic studies were carried out with the wild type enzyme and with the C13S mutant enzyme, which catalyzes only the initial steps in the reaction. Three findings eliminate the possibility of a nucleophilic aromatic substitution reaction. First, the product of such a reaction, 2,3,5-trichloro-6-S-glutathionylhydroquinone, is not a kinetically competent intermediate. Second, the enzyme can carry out the reaction when the substrate is deprotonated at the active site. Nucleophilic aromatic substitution should not be possible when the substrate is negatively charged. Third, substantial normal solvent kinetic isotope effects on k(cat) and k(cat)/K(M,TriCHQ) are observed. Nonenzymatic and enzymatic nucleophilic S(N)Ar reactions typically show inverse solvent kinetic isotope effects.
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PMID:The reaction catalyzed by tetrachlorohydroquinone dehalogenase does not involve nucleophilic aromatic substitution. 1180 31

Tetrachlorohydroquinone (TCHQ) dehalogenase catalyzes the conversion of TCHQ to 2,6-dichlorohydroquinone during degradation of pentachlorophenol by Sphingobium chlorophenolicum. TCHQ dehalogenase is a member of the glutathione S-transferase superfamily. Members of this superfamily typically catalyze nucleophilic attack of glutathione upon an electrophilic substrate to form a glutathione conjugate and contain a single glutathione binding site in each monomer of the typically dimeric enzyme. TCHQ dehalogenase, in contrast to most members of the superfamily, is a monomer and uses 2 equiv of glutathione to catalyze a more complex reaction. The first glutathione is involved in formation of a glutathione conjugate, while the second is involved in the final step of the reaction, a thiol-disulfide exchange reaction that regenerates the free enzyme and forms GSSG. TCHQ dehalogenase is severely inhibited by its aromatic substrates, TCHQ and trichlorohydroquinone (TriCHQ). TriCHQ acts as a noncompetitive inhibitor of the thiol-disulfide exchange reaction required to regenerate the free form of the enzyme. In addition, dissociation of the GSSG product is inhibited by TriCHQ. The thiol-disulfide exchange reaction is the rate-limiting step in the reductive dehalogenation reaction under physiological conditions.
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PMID:Mechanism of the severe inhibition of tetrachlorohydroquinone dehalogenase by its aromatic substrates. 1735 22