| Development and evaluation of a boronate inhibitor of gamma-glutamyl transpeptidase. | |
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MedLine Citation:
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PMID: 11368005 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Gamma-glutamyl transpeptidase (gamma-GT) plays a central role in the metabolism of glutathione and is also a marker for neoplasia and cell transformation. We have investigated the compound L-2-amino-4-boronobutanoic acid (ABBA) as a structural analog of the putative ternary complex formed by the enzyme, L-serine, and borate, proposed to function as a transition state analog inhibitor. ABBA was found to be a potent inhibitor of the enzyme, with Ki = 17 nM using typical assay conditions (pH 8, gamma-glutamyl-p-nitroanilide substrate, 20 mM glycyl-glycine acceptor). ABBA is a stable amino acid analog with pK values determined from 13C and 11B NMR to be 2.3, 11.0 (amino titration), and 7.9 (boronate titration). The structural similarity to glutamate suggested that it might function as a glutamate analog for some glutamate-dependent enzymes or receptors. Transamination of pyruvate by ABBA to yield alanine in the presence of glutamic pyruvic transaminase was demonstrated by 13C NMR. The 2-keto-4-boronobutanoic acid transamination product is apparently fairly labile to hydrolysis, leading to formation of 2-ketobutanoic acid plus borate. The latter is also subsequently transaminated to yield 2-aminobutanoic acid. Both of these metabolites were observed in the 13C NMR spectrum. However, the corresponding transamination of oxaloacetate by ABBA in the presence of glutamic oxaloacetic transaminase was not observed. Effects of ABBA on the growth of cultured rat liver cell lines ARL-15C1 (nontumorigenic, low gamma-GT activity) and ARL-16T2 (tumorigenic, high gamma-GT activity) were also investigated, both in standard Williams Media as well as in a low cysteine growth medium. A high concentration (1 mM) of ABBA inhibited the growth of both cell lines in both media, with the degree of inhibition greater in the low cysteine medium. Alternatively, growth inhibition by 10 microM ABBA could be observed only in the low cysteine media. In general, there were no significant differences between the two cell lines in terms of sensitivity to ABBA. |
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Authors:
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R E London; S A Gabel |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Archives of biochemistry and biophysics Volume: 385 ISSN: 0003-9861 ISO Abbreviation: Arch. Biochem. Biophys. Publication Date: 2001 Jan |
Date Detail:
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Created Date: 2001-05-22 Completed Date: 2001-06-07 Revised Date: 2012-01-25 |
Medline Journal Info:
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Nlm Unique ID: 0372430 Medline TA: Arch Biochem Biophys Country: United States |
Other Details:
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Languages: eng Pagination: 250-8 Citation Subset: IM |
Affiliation:
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Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. london@niehs.nih.gov |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alanine
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metabolism Alanine Transaminase / metabolism Aminobutyric Acids / metabolism Animals Aspartate Aminotransferases / metabolism Binding Sites Boron Compounds / chemistry, pharmacology* Carbon Isotopes Cell Division / drug effects Cell Line Culture Media / chemistry, pharmacology Cysteine / pharmacology Glutamine / analogs & derivatives*, metabolism Hydrogen-Ion Concentration Kinetics Liver Magnetic Resonance Spectroscopy Oxaloacetate / metabolism Protons Pyruvic Acid / metabolism Rats gamma-Glutamyltransferase / antagonists & inhibitors*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/2-amino-4-boronobutanoic acid; 0/Aminobutyric Acids; 0/Boron Compounds; 0/Carbon Isotopes; 0/Culture Media; 0/Oxaloacetate; 0/Protons; 127-17-3/Pyruvic Acid; 52-90-4/Cysteine; 56-41-7/Alanine; 56-85-9/Glutamine; 7300-59-6/gamma-glutamine-4-nitroanilide; 80-60-4/alpha-aminobutyric acid; EC 2.3.2.2/gamma-Glutamyltransferase; EC 2.6.1.1/Aspartate Aminotransferases; EC 2.6.1.2/Alanine Transaminase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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