PMID- 17167048
OWN - NLM
STAT- MEDLINE
DCOM- 20070508
LR  - 20081121
IS  - 0021-924X (Print)
IS  - 0021-924X (Linking)
VI  - 141
IP  - 1
DP  - 2007 Jan
TI  - Analysis of inhibition rate enhancement by covalent linkage of antithrombin to 
      heparin as a potential predictor of reaction mechanism.
PG  - 25-35
AB  - Antithrombin (AT) inhibition of coagulation enzymes is catalyzed by 
      unfractionated heparin (UFH) and other heparinoids. Reaction proceeds either via 
      conformational activation of the inhibitor or template-mediated binding of both 
      inhibitor and protease. We investigated if the relative inhibition rates of AT + 
      UFH and covalent AT-heparin conjugate (ATH) with coagulation factors might be 
      indicative of the mechanism involved. Rates were determined by discontinuous 
      assay and mechanisms were probed by a variety of binding studies with UFH or ATH 
      heparin chains. Rates were increased more than 2-fold with ATH over AT + UFH in 
      reactions with thrombin, factor (F) VIIa + tissue factor + Ca2+ + lipid, FIXa and 
      FXIa, but not with FXa or FXIIa. In comparison, UFH or ATH heparin binding 
      (evidence of a template mechanism) was only observed with thrombin, tissue 
      factor, FIXa and FXIa. Thus, inhibition rate enhancement by conjugation of AT 
      with heparin were predictive of inhibitor.enzyme template bridging by heparin. 
      Rationales behind this novel concept are discussed.
FAU - Patel, Sanjay
AU  - Patel S
AD  - Henderson Research Centre, 711 Concession Street, Hamilton, Canada L8V 1C3.
FAU - Berry, Leslie R
AU  - Berry LR
FAU - Chan, Anthony K C
AU  - Chan AK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20061213
PL  - England
TA  - J Biochem
JT  - Journal of biochemistry
JID - 0376600
RN  - 0 (Antithrombins)
RN  - 0 (Blood Coagulation Factors)
RN  - 9005-49-6 (Heparin)
RN  - 9035-58-9 (Thromboplastin)
RN  - EC 3.4.21.21 (Factor VIIa)
RN  - EC 3.4.21.22 (Factor IXa)
RN  - EC 3.4.21.27 (Factor XIa)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Antithrombins/*chemistry/*metabolism
MH  - Blood Coagulation Factors/*antagonists & inhibitors/metabolism
MH  - Factor IXa/antagonists & inhibitors/metabolism
MH  - Factor VIIa/antagonists & inhibitors/metabolism
MH  - Factor XIa/antagonists & inhibitors/metabolism
MH  - Heparin/*chemistry/*metabolism
MH  - Hot Temperature
MH  - Kinetics
MH  - Thrombin/antagonists & inhibitors/metabolism
MH  - Thromboplastin/antagonists & inhibitors/metabolism
EDAT- 2006/12/15 09:00
MHDA- 2007/05/09 09:00
CRDT- 2006/12/15 09:00
PHST- 2006/12/15 09:00 [pubmed]
PHST- 2007/05/09 09:00 [medline]
PHST- 2006/12/15 09:00 [entrez]
AID - mvm001 [pii]
AID - 10.1093/jb/mvm001 [doi]
PST - ppublish
SO  - J Biochem. 2007 Jan;141(1):25-35. doi: 10.1093/jb/mvm001. Epub 2006 Dec 13.