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rdf:type |
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lifeskim:mentions |
umls-concept:C0015501,
umls-concept:C0017262,
umls-concept:C0033706,
umls-concept:C0040048,
umls-concept:C0178555,
umls-concept:C0185117,
umls-concept:C0205148,
umls-concept:C0441655,
umls-concept:C0596901,
umls-concept:C0679209,
umls-concept:C1704675,
umls-concept:C1708096,
umls-concept:C2698651,
umls-concept:C2911684
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pubmed:issue |
3
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pubmed:dateCreated |
2008-3-10
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pubmed:abstractText |
Incorporation of factor (F) Va into prothrombinase directs prothrombin activation by FXa through the meizothrombin pathway, characterized by initial cleavage at Arg(320). We have shown that a pentapeptide with the sequence DYDYQ specifically inhibits this pathway. It has been also established that Hir(54-65)(SO(3)(-)) is a specific inhibitor of prothrombinase. To understand the role of FVa within prothrombinase at the molecular level, we have studied thrombin formation by prothrombinase in the presence of various prothrombin-derived fragments alone or in combination. Activation of prethrombin 1 is slow with cleavages at Arg(320) and Arg(271) occurring with similar rates. Addition of purified fragment 1 to prethrombin 1 accelerates both the rate of cleavage at Arg(320) and thrombin formation. Both reactions were inhibited by Hir(54-65)(SO(3)(-)) while DYDYQ had no significant inhibitory effect on prethrombin 1 cleavage in the absence or presence of fragment 1. Similarly, activation of prethrombin 2 by prothrombinase, is inhibited by Hir(54-65)(SO(3)(-)), but is not affected by DYDYQ. Addition of purified fragment 1*2 to prethrombin 2 accelerates the rate of cleavage at Arg(320) by prothrombinase. This addition also results in a significant inhibition of thrombin formation by DYDYQ and is concurrent with the elimination of the inhibitory effect of Hir(54-65)(SO(3)(-)) on the same reaction. Finally, a membrane-bound ternary complex composed of prethrombin 2/fragment 1*2/Hir(54-65)(SO(3)(-)) is inhibited by DYDYQ. Altogether, the data demonstrate that membrane-bound fragment 1 is required to promote optimum Fva cofactor activity which in turn is translated by efficient initial cleavage of prothrombin by prothrombinase at Arg(320).
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Arginine,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Precursors,
http://linkedlifedata.com/resource/pubmed/chemical/Factor V,
http://linkedlifedata.com/resource/pubmed/chemical/Factor Va,
http://linkedlifedata.com/resource/pubmed/chemical/Factor Xa,
http://linkedlifedata.com/resource/pubmed/chemical/Hirudins,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Precursors,
http://linkedlifedata.com/resource/pubmed/chemical/Prothrombin,
http://linkedlifedata.com/resource/pubmed/chemical/Thrombin,
http://linkedlifedata.com/resource/pubmed/chemical/Thromboplastin,
http://linkedlifedata.com/resource/pubmed/chemical/meizothrombin,
http://linkedlifedata.com/resource/pubmed/chemical/prethrombins,
http://linkedlifedata.com/resource/pubmed/chemical/prothrombin fragment 1,
http://linkedlifedata.com/resource/pubmed/chemical/prothrombin fragment 1.2,
http://linkedlifedata.com/resource/pubmed/chemical/prothrombinase complex
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0340-6245
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
99
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
511-22
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pubmed:meshHeading |
pubmed-meshheading:18327399-Arginine,
pubmed-meshheading:18327399-Binding Sites,
pubmed-meshheading:18327399-Cell Membrane,
pubmed-meshheading:18327399-Cells, Cultured,
pubmed-meshheading:18327399-Endothelial Cells,
pubmed-meshheading:18327399-Enzyme Inhibitors,
pubmed-meshheading:18327399-Enzyme Precursors,
pubmed-meshheading:18327399-Factor V,
pubmed-meshheading:18327399-Factor Va,
pubmed-meshheading:18327399-Factor Xa,
pubmed-meshheading:18327399-Hirudins,
pubmed-meshheading:18327399-Humans,
pubmed-meshheading:18327399-Kinetics,
pubmed-meshheading:18327399-Models, Molecular,
pubmed-meshheading:18327399-Peptide Fragments,
pubmed-meshheading:18327399-Protein Binding,
pubmed-meshheading:18327399-Protein Conformation,
pubmed-meshheading:18327399-Protein Precursors,
pubmed-meshheading:18327399-Prothrombin,
pubmed-meshheading:18327399-Thrombin,
pubmed-meshheading:18327399-Thromboplastin
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pubmed:year |
2008
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pubmed:articleTitle |
The interaction of fragment 1 of prothrombin with the membrane surface is a prerequisite for optimum expression of factor Va cofactor activity within prothrombinase.
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pubmed:affiliation |
Cleveland State University, Department of Chemistry, OH 44115, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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