Document Detail


Inactivation of mouse liver glutathione S-transferase YfYf (Pi class) by ethacrynic acid and 5,5'-dithiobis-(2-nitrobenzoic acid).
MedLine Citation:
PMID:  8363586     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mouse liver glutathione S-transferase YfYf (Pi class) reacts with [14C]ethacrynic acid to form a covalent adduct with a stoichiometry of 1 mol per mol of subunit. Proteolytic digestion of the enzyme-[14C]ethacrynic acid adduct with V8 protease produced an 11 kDa fragment containing radioactivity. Sequencing revealed this to be an N-terminal peptide (minus the first 15 residues, terminating at Glu-112) which contains only one cysteine residue (Cys-47). This is tentatively identified as the site of ethacrynic attachment. Kinetic studies reveal that glutathione S-conjugates protect against inactivation by ethacrynic acid, but the level of protection is not consistent with their potency as product inhibitors. A model is proposed in which glutathione S-conjugates and ethacrynic acid compete for the free enzyme, and a second molecule of ethacrynic acid reacts covalently with the enzyme-ethacrynic acid complex. The native protein contains one thiol reactive with 5,5'-dithiobis-(2-nitrobenzoic acid) at neutral pH. The resultant mixed disulphide, like the ethacrynic acid adduct, is inactive, but treatment with cyanide (which incorporates on a mol for mol basis) restores activity to 35% of that of the native enzyme.
Authors:
M F Phillips; T J Mantle
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  294 ( Pt 1)     ISSN:  0264-6021     ISO Abbreviation:  Biochem. J.     Publication Date:  1993 Aug 
Date Detail:
Created Date:  1993-09-24     Completed Date:  1993-09-24     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  57-62     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Trinity College, Dublin, Ireland.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Dithionitrobenzoic Acid / pharmacology*
Ethacrynic Acid / antagonists & inhibitors,  pharmacology*
Glutathione / analogs & derivatives,  pharmacology
Glutathione Transferase / antagonists & inhibitors*,  chemistry
Hydrogen-Ion Concentration
Isoenzymes / antagonists & inhibitors*,  chemistry
Kinetics
Liver / enzymology*
Mice
Molecular Sequence Data
Peptide Fragments / chemistry
Peptide Mapping
Sulfhydryl Compounds / chemistry
Chemical
Reg. No./Substance:
0/Isoenzymes; 0/Peptide Fragments; 0/Sulfhydryl Compounds; 26289-39-4/S-(2,4-dinitrophenyl)glutathione; 2922-56-7/S-methyl glutathione; 58-54-8/Ethacrynic Acid; 69-78-3/Dithionitrobenzoic Acid; 70-18-8/Glutathione; EC 2.5.1.18/Glutathione Transferase
Comments/Corrections

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