Mechanisms and specificity of factor XIa and trypsin inhibition by protease nexin 2 and basic pancreatic trypsin inhibitor.
J Biochem
; 148(4): 467-79, 2010 Oct.
Article
en En
| MEDLINE
| ID: mdl-20647553
ABSTRACT
Factor XIa (FXIa) inhibition by protease nexin-2 (PN2KPI) was compared with trypsin inhibition by basic pancreatic trypsin inhibitor (BPTI). PN2KPI was a potent inhibitor of FXIa (K(i) â¼ 0.81 nM) and trypsin (K(i) â¼ 0.03 nM), but not of other coagulation proteases (thrombin, FVIIa, FIXa, FXa, FXIIa, plasmin, kallikrein, K(i) > 185 nM). PN2KPI was â¼775-fold more potent than BPTI in FXIa inhibition, but both exhibited similar potencies against trypsin. Studies of FXIa and trypsin inhibition by PN2KPI and BPTI and P1 site swap mutants (PN2KPI-R15 K, BPTI-K15 R) demonstrated that FXIa inhibition by PN2KPI and P1 site swap mutants and trypsin inhibition by PN2KPI and BPTI conform to a single-step, slow equilibration inhibitory mechanism, whereas FXIa-inhibition by BPTI follows a classical, competitive inhibitory mechanism. Mutation of P1 impaired FXIa inhibition by PN2KPI-R15 K â¼14-fold, enhanced FXIa inhibition by BPTI-K15 R â¼150-fold, and had no effect on trypsin inhibition. Arginine at the P1 site of either PN2KPI or BPTI confers high affinity and specificity for FXIa, whereas either arginine or lysine suffices for trypsin inhibition. Thus, PN2KPI is a highly specific inhibitor of FXIa among coagulation enzymes, but the flexibility of trypsin renders it susceptible to inhibition by both wild-type and mutant forms of PN2KPI and BPTI.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tripsina
/
Factor XIa
/
Inhibidores de Tripsina
/
Aprotinina
/
Precursor de Proteína beta-Amiloide
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Biochem
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos