PMID- 23172304
OWN - NLM
STAT- MEDLINE
DCOM- 20130808
LR  - 20211021
IS  - 1756-2651 (Electronic)
IS  - 0021-924X (Print)
IS  - 0021-924X (Linking)
VI  - 153
IP  - 2
DP  - 2013 Feb
TI  - P1 and P2' site mutations convert protease nexin-2 from a factor XIa inhibitor to 
      a plasmin inhibitor.
PG  - 221-31
LID - 10.1093/jb/mvs133 [doi]
AB  - The kunitz protease inhibitor domain of PN2 (PN2KPI) is a potent and specific 
      inhibitor (K(i) 0.5-2 nM) of factor XIa (FXIa) and inhibits cerebrovascular 
      thrombosis in mice. To determine whether the antithrombotic properties of PN2KPI 
      arise from its FXIa-inhibitory activity, we have now prepared mutant forms of 
      PN2KPI. Mutations at the P1 (Arg(15)) site in combination with P2' (Met(17)) 
      mutations profoundly affect inhibition of FXIa, plasmin, kallikrein, factor Xa 
      and thrombin. The mutant proteins PN2KPI-R(15)K, -M(17)K, -R(15)K,M(17)K and 
      -R(15)K,M(17)R lost inhibitory activity against FXIa (K(i) 34, 94, 3081 and 707 
      nM, respectively) and kallikrein (no inhibition) and gained inhibitory activity 
      against plasmin (K(i) 108, 7, 8 and 8 nM, respectively). The intravenous 
      administration of rPN2KPI into mice dramatically decreased thrombus formation in 
      a murine model of FeCl(3)-induced carotid injury, whereas rPN2KPI-R(15)K,M(17)K 
      failed to inhibit thrombus formation. Molecular modelling studies showed that 
      fine structural variations explain the observed functional differences in FXIa 
      and plasmin inhibition. PN2KPI has potent antithrombotic activity due to its 
      specific FXIa anticoagulant activity, whereas PN2KPI-R(15)K,M(17)K and 
      PN2KPI-R(15)K,M(17)R have potent antifibrinolytic (antiplasmin) activity without 
      anticoagulant or antithrombotic activity.
FAU - Navaneetham, Duraiswamy
AU  - Navaneetham D
AD  - The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 
      Philadelphia, PA 19140, USA.
FAU - Wu, Wenman
AU  - Wu W
FAU - Li, Hongbo
AU  - Li H
FAU - Sinha, Dipali
AU  - Sinha D
FAU - Tuma, Ronald F
AU  - Tuma RF
FAU - Walsh, Peter N
AU  - Walsh PN
LA  - eng
GR  - HL46213/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20121120
PL  - England
TA  - J Biochem
JT  - Journal of biochemistry
JID - 0376600
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Antifibrinolytic Agents)
RN  - EC 3.4.21.27 (Factor XIa)
SB  - IM
MH  - Amyloid beta-Protein Precursor/genetics/*metabolism/*pharmacology
MH  - Animals
MH  - Antifibrinolytic Agents/*metabolism/*pharmacology
MH  - Factor XIa/*antagonists & inhibitors
MH  - Female
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mutation
PMC - PMC3555081
EDAT- 2012/11/23 06:00
MHDA- 2013/08/09 06:00
PMCR- 2014/02/01
CRDT- 2012/11/23 06:00
PHST- 2012/11/23 06:00 [entrez]
PHST- 2012/11/23 06:00 [pubmed]
PHST- 2013/08/09 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - mvs133 [pii]
AID - 10.1093/jb/mvs133 [doi]
PST - ppublish
SO  - J Biochem. 2013 Feb;153(2):221-31. doi: 10.1093/jb/mvs133. Epub 2012 Nov 20.