Mechanisms and specificity of factor XIa and trypsin inhibition by protease nexin 2 and basic pancreatic trypsin inhibitor.

Journal of Biochemistry
Duraiswamy NavaneethamPeter N Walsh

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) ∼ 0.81 nM) and trypsin (K(i) ∼ 0.03 nM), but not of other coagulation proteases (thrombin, FVIIa, FIXa, FXa, FXIIa, plasmin, kallikrein, K(i) > 185 nM). PN2KPI was ∼775-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 ∼14-fold, enhanced FXIa inhibition by BPTI-K15 R ∼150-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 flexibili...Continue Reading

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Citations

Sep 24, 2010·The Journal of Biological Chemistry·Moh'd A SalamehEvette S Radisky
Nov 23, 2012·Journal of Biochemistry·Duraiswamy NavaneethamPeter N Walsh
Jun 19, 2013·Marine Drugs·Caroline B F Mourão, Elisabeth F Schwartz
Sep 15, 2012·Journal of Structural Biology·Rossana García-FernándezLars Redecke
Mar 20, 2016·Protein Expression and Purification·Rossana García-FernándezMaría de Los Ángeles Chávez
Feb 4, 2012·Journal of Enzyme Inhibition and Medicinal Chemistry·Agnieszka MarkowskaKrystyna Midura-Nowaczek
May 7, 2013·Annual Review of Biomedical Engineering·Thomas V ColaceScott L Diamond
Nov 5, 2016·The Journal of Biological Chemistry·Olumide KayodeEvette S Radisky
Aug 5, 2018·Blood Reviews·Benjamin F TillmanDavid Gailani

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