Document Detail


Two naturally occurring variants of TAFI (Thr-325 and Ile-325) differ substantially with respect to thermal stability and antifibrinolytic activity of the enzyme.
MedLine Citation:
PMID:  11684677     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Thrombin-activable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like zymogen that is activated to TAFIa by plasmin, thrombin, or the thrombin-thrombomodulin complex. The enzyme TAFIa attenuates clot lysis by removing lysine residues from a fibrin clot. Screening of nine human cDNA libraries indicated a common variation in TAFI at position 325 (Ile-325 or Thr-325). This is in addition to the variation at amino acid position 147 (Ala-147 or Thr-147) characterized previously. Thus, four variants of TAFI having either Ala or Thr at position 147 and either Thr or Ile at position 325 were stably expressed in baby hamster kidney cells and purified to homogeneity. The kinetics of activation of TAFI by thrombin/thrombomodulin were identical for all four variants; however, Ile at position 325 extended the half-life of TAFIa from 8 to 15 min at 37 degrees C, regardless of the residue at position 147. In clot lysis assays with thrombomodulin and the TAFI variants, or with pre-activated TAFI variants, the Ile-325 variants exhibited an antifibrinolytic effect that was 60% greater than the Thr-325 variants. Similarly, in the absence of thrombomodulin, the Ile-325 variants exhibited an antifibrinolytic effect that was 30-50% greater than the Thr-325 variants. In contrast, the variation at position 147 had little if any effect on the antifibrinolytic potential of TAFIa. The increased antifibrinolytic potential of the Ile-325-containing TAFI variants reflects the fact that these variants have an increased ability to mediate the release of lysine from partially degraded fibrin and suppress plasminogen activation. These findings imply that individuals homozygous for the Ile-325 variant of TAFI would likely have a longer lived and more potent TAFIa enzyme than those homozygous for the Thr-325 variant.
Authors:
Mark Schneider; Michael Boffa; Ronald Stewart; Mona Rahman; Marlys Koschinsky; Michael Nesheim
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Publication Detail:
Type:  Journal Article     Date:  2001-10-29
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Jan 
Date Detail:
Created Date:  2002-01-07     Completed Date:  2002-02-07     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1021-30     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Azo Compounds / metabolism
Blood Coagulation / physiology
Carboxypeptidase U / chemistry,  genetics,  metabolism*
Cell Line
Cricetinae
Enzyme Activation
Enzyme Stability
Fibrinogen / metabolism
Fibrinolytic Agents / metabolism*
Gene Library
Genetic Variation*
Hemostatics / metabolism
Humans
Lysine / analogs & derivatives
Plasma / chemistry
Plasminogen / metabolism
Recombinant Proteins / metabolism
Temperature
Thrombin / antagonists & inhibitors,  metabolism*
Tissue Plasminogen Activator / metabolism
Chemical
Reg. No./Substance:
0/Azo Compounds; 0/Fibrinolytic Agents; 0/Hemostatics; 0/Recombinant Proteins; 56-87-1/Lysine; 9001-32-5/Fibrinogen; 9001-91-6/Plasminogen; EC 3.4.17.20/Carboxypeptidase U; EC 3.4.21.5/Thrombin; EC 3.4.21.68/Tissue Plasminogen Activator

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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