Source:http://linkedlifedata.com/resource/pubmed/id/12929424
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
2
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pubmed:dateCreated |
2003-8-21
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pubmed:abstractText |
A series of brominated compounds has been synthesized and evaluated as substrates and inhibitors of kynureninase from Pseudomonas fluorescens. Both 3-bromo-L-kynurenine and 5-bromo-L-kynurenine were found to be substrates with similar k(cat) values to L-kynurenine, but the K(m) value for 3-bromo-L-kynurenine is very high (ca. 2 mM) compared to that for 5-bromo-L-kynurenine (11 microM) and L-kynurenine (25 microM). Both isomers of bromokynurenine react with kynureninase within the dead time of the stopped-flow instrument (ca. 1 ms) to form quinonoid intermediates with a lambda max of 494 nm that decay with rate constants of 300-600 s-1, similar to L-kynurenine. The two diastereomers of 5-bromodihydro-L-kynurenine were also prepared, and are more potent inhibitors than dihydro-L-kynurenines. (4R)-5-Bromodihydro-L-kynurenine is one of the most potent inhibitors of P. fluorescens kynureninase found to date (Ki = 55 nM) and also acts as a slow substrate; the (4S)-epimer, on the other hand, shows no measurable substrate activity, but it is a potent competitive inhibitor with a Ki value of 170 nM. In contrast, brominated analogs of (S)-(2-aminophenyl)-L-cysteine S,S-dioxide, (S)-(2-amino-4-bromophenyl)-L-cysteine S,S-dioxide and (S)-(2-amino-5-bromophenyl)-L-cysteine S,S-dioxide are competitive inhibitors of kynureninase, with Ki values of about 300 and 400 nm, respectively, about ten-fold higher than the value of 27 nM obtained for the parent compound. These results suggest that the binding modes of substrates and the various classes of inhibitors in the active site of kynureninase are different.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Hydrocarbons, Brominated,
http://linkedlifedata.com/resource/pubmed/chemical/Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Kynurenine,
http://linkedlifedata.com/resource/pubmed/chemical/kynureninase
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1477-0520
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
21
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pubmed:volume |
1
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
288-95
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:12929424-Binding, Competitive,
pubmed-meshheading:12929424-Cysteine,
pubmed-meshheading:12929424-Enzyme Inhibitors,
pubmed-meshheading:12929424-Hydrocarbons, Brominated,
pubmed-meshheading:12929424-Hydrolases,
pubmed-meshheading:12929424-Kinetics,
pubmed-meshheading:12929424-Kynurenine,
pubmed-meshheading:12929424-Nuclear Magnetic Resonance, Biomolecular,
pubmed-meshheading:12929424-Pseudomonas fluorescens,
pubmed-meshheading:12929424-Spectrophotometry,
pubmed-meshheading:12929424-Stereoisomerism,
pubmed-meshheading:12929424-Structure-Activity Relationship,
pubmed-meshheading:12929424-Substrate Specificity
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pubmed:year |
2003
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pubmed:articleTitle |
Differential effects of bromination on substrates and inhibitors of kynureninase from Pseudomonas fluorescens.
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pubmed:affiliation |
Department of Chemistry, University of Georgia, Athens, Georgia 30602-2556, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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