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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
1
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pubmed:dateCreated |
1995-3-29
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pubmed:abstractText |
Aspirin causes a time-dependent inhibition of prostaglandin endoperoxide H synthases (PGHS)-1 and -2 by acetylating active site serines present in both isozymes. In the case of PGHS-1, aspirin acetylation blocks cyclooxygenase activity, apparently by preventing arachidonate binding to the cyclooxygenase active site. With PGHS-2, acetylation does not block substrate binding but rather alters the enzyme in such a way that the acetylated form of PGHS-2 produces 15R-hydroxyeicosatetraenoic acid (15R-HETE) instead of the usual prostaglandin endoperoxide product. Based on these differences between PGHS-1 and PGHS-2, we reasoned that a salicylate ester containing an acyl group somewhat larger than the acetyl group of aspirin might be a selective inhibitor of PGHS-2. Accordingly, we prepared and tested eight different acyl salicylates as inhibitors of human (h) PGHS-1 and -2 expressed transiently in cos-1 cells. Valeryl(pentanoyl)salicylate (VSA) was the only compound in this series which showed isozyme selectivity, and, surprisingly, VSA inhibited hPGHS-1 much more effectively than hPGHS-2. Inhibition of hPGHS-1 by VSA was time-dependent. VSA also inhibited ovine PGHS-1 but did not inhibit the S530A mutant of ovine PGHS-1. This latter mutant, which lacks the active site serine hydroxyl group, is also refractory to inhibition by acetylsalicylate. Thus, we conclude that VSA acylates the active site serine of PGHS-1. VSA inhibited prostanoid synthesis by serum-starved murine NIH 3T3 cells which express only PGHS-1; in contrast, VSA caused only partial inhibition of prostanoid synthesis by serum-stimulated 3T3 cells which express both PGHS isozymes. Our results establish that VSA can be used as a reasonably selective inhibitor of PGHS-1.
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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/Cyclooxygenase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Prostaglandin-Endoperoxide Synthases,
http://linkedlifedata.com/resource/pubmed/chemical/Prostaglandins,
http://linkedlifedata.com/resource/pubmed/chemical/Salicylic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Salicylic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Serine
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0003-9861
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
20
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pubmed:volume |
317
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
19-24
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:7872783-3T3 Cells,
pubmed-meshheading:7872783-Animals,
pubmed-meshheading:7872783-Binding Sites,
pubmed-meshheading:7872783-Cattle,
pubmed-meshheading:7872783-Cells, Cultured,
pubmed-meshheading:7872783-Cyclooxygenase Inhibitors,
pubmed-meshheading:7872783-Humans,
pubmed-meshheading:7872783-Mice,
pubmed-meshheading:7872783-Prostaglandin-Endoperoxide Synthases,
pubmed-meshheading:7872783-Prostaglandins,
pubmed-meshheading:7872783-Salicylic Acid,
pubmed-meshheading:7872783-Salicylic Acids,
pubmed-meshheading:7872783-Serine,
pubmed-meshheading:7872783-Sheep
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pubmed:year |
1995
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pubmed:articleTitle |
Selective inhibition of prostaglandin endoperoxide synthase-1 (cyclooxygenase-1) by valerylsalicylic acid.
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pubmed:affiliation |
Department of Biochemistry, Michigan State University, East Lansing 48824.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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