Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An early event in the nephrotoxicity of haloalkene cysteine conjugates is their metabolism by cysteine conjugate beta-lyase to generate a reactive "thiol moiety" which binds to protein. This reactive metabolite(s) has been reported to cause mitochondrial dysfunction. We have examined the effect of three haloalkene cysteine conjugates on the activity of rat renal cortical cytosolic glutathione reductase and mitochondrial lipoyl dehydrogenase, two enzymes which have been reported to be inhibited by S-(1,2-dichlorovinyl)-L-cysteine (DCVC) in the liver. N-Acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L- cysteine (N-acetyl PCBC) produced a time- and concentration-dependent inhibition of glutathione reductase and kinetic studies showed that the inhibition was noncompetitive with a Ki of 215 microM. The enzyme activity from male rat kidney was more sensitive to N-acetyl PCBC than that from female rat kidney. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, and bis-p-nitrophenyl phosphate, an amidase inhibitor, blocked the effect of N-acetyl PCBC on glutathione reductase, indicating that metabolism by the cytosol is required to produce enzyme inhibition. S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine (TFEC) and DCVC are also noncompetitive inhibitors of glutathione reductase but are less active than N-acetyl PCBC with Ki's of 2.6 and 6.2 mM for DCVC and TFEC, respectively, DCVC produced a time- and concentration-dependent inhibition of lipoyl dehydrogenase and kinetic studies showed that the inhibition was noncompetitive with a Ki of 762 microM. TFEC and PCBC also inhibit lipoyl dehydrogenase. Aminooxyacetic acid blocked the effect of DCVC, TFEC, and PCBC on lipoyl dehydrogenase, indicating that metabolism by the mitochondrial fraction is required to produce enzyme inhibition. Glutathione reductase activity in the renal cortex of male rats treated with 200 mg/kg hexachloro-1,3-butadiene (HCBD) was inhibited as early as 1 hour after dosing, before signs of marked morphological damage. The activity of lipoyl dehydrogenase was also reduced but was only statistically significant 8 hr after dosing when there was marked renal dysfunction. These findings indicate that the reactive thiol moiety formed by cysteine conjugate beta-lyase cleavage of PCBC can inhibit both glutathione reductase and lipoyl dehydrogenase activities in vivo following HCBD administration. We suggest that such inhibition is a general phenomenon, occurring with diverse and as yet unidentified renal proteins. The critical nature of mitochondrial function and the generation of reactive metabolites within this compartment make this organelle a prime target.
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PMID:The effect of haloalkene cysteine conjugates on rat renal glutathione reductase and lipoyl dehydrogenase activities. 236 Feb 7

The product resulting from the reaction between E-2-hexenal and l-cysteine was shown to be a diastereoisomeric mixture of 2-(2-S-l-cysteinylpentyl)-1,3-thiazolidine-4-carboxylic acid 1. Treatment of the conjugate with two sources of cysteine-S-conjugate beta-lyase (tryptophanase from E. coli and a crude enzyme extract prepared from Eubacterium limosum) resulted in the formation of 3-mercaptohexanal. The reaction proceeded with a slight preference for the (S)-configured product, however, with low conversion rate. The role of 3-S-l-cysteinylhexanal 2 as substrate for beta-lyases was demonstrated by in situ generation of 2 from 3-S-(N-acetyl-l-cysteinyl)hexanal using acylase. Opposite enantioselectivity was observed for the liberation of 3-mercaptohexanol from 3-S-l-cysteinylhexanol 5 by the enzyme preparations from Eubacterium limosum and tryptophanase. Various yeasts produced 3-mercaptohexanol starting from 1 as well as from 5. The reactions proceeded without preferential formation of one of the enantiomers.
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PMID:Stereochemical course of the generation of 3-mercaptohexanal and 3-mercaptohexanol by beta-lyase-catalyzed cleavage of cysteine conjugates. 1470 22