BJ-48, a novel thrombin-like enzyme from the Bothrops jararacussu venom with high selectivity for Arg over Lys in P1: Role of N-glycosylation in thermostability and active site accessibility

Toxicon. 2007 Jul;50(1):18-31. doi: 10.1016/j.toxicon.2007.02.018. Epub 2007 Mar 7.

Abstract

BJ-48, a serine protease from the venom of Bothrops jararacussu, was purified to homogeneity using affinity chromatography on p-aminobenzamidine-agarose followed by HPLC gel filtration. BJ-48 presented 52kDa by SDS-PAGE analysis and 48,036Da by electron spray mass spectrometry. The enzyme was shown to be highly glycosylated with 42% of N-linked carbohydrates composed of Fuc(1):GalN(4):GlcN(5):Gal(1):Man(2) and a high content of sialic acid residues (8-12%). BJ-48 had optimal esterase activity at pH 7.5 and displayed maximum catalytic rate at 50 degrees C. Its hydrolytic activity was strongly inhibited by aprotinin and dithiothreitol while N-tosyl-l-phenylalanine chloromethyl ketone, 6-aminocaproic acid, E-64 and soybean trypsin inhibitor (SBTI) were ineffective. The kinetics of BJ-48 with chromogenic substrates revealed an unprecedented selectivity (10(4)-fold) for Arg over Lys in P1. BJ-48 proved to be a thrombin-like enzyme (TLE) with a specific fibrinogen-clotting activity of 73.4NIH units/mg. The TLE rapidly digested human fibrinogen Bbeta chain, but the Aalpha chain was cleaved specifically to release fibrinopeptide A with k(cat)/K(m)=2.1 microM(-1)s(-1). The TLE showed no activity toward other thrombin substrates like protein C, protease-activated receptor-1 or inhibitors such as hirudin and antithrombin. A non-denaturing procedure using PNGase F and neuraminidase followed by hydrophobic interaction chromatography was employed to obtain active BJ-48 forms with variable carbohydrate content. Compared to the native enzyme, total or partially deglycosylated BJ-48 forms presented up to 2-fold reduction in their specific activities upon heating at 55/65 degrees C or treatment with SBTI. These results point out a role for BJ-48 glycosylation in thermostability and controlling the access of some canonical protein inhibitors to the active site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / metabolism
  • Bothrops / metabolism*
  • Catalytic Domain
  • Chromatography, Affinity
  • Chromatography, Gel
  • Chromatography, High Pressure Liquid
  • Crotalid Venoms / antagonists & inhibitors
  • Crotalid Venoms / chemistry*
  • Crotalid Venoms / metabolism
  • Enzyme Stability
  • Fibrinogen / metabolism
  • Glycosylation
  • Hydrogen-Ion Concentration
  • Lysine / metabolism
  • Serine Endopeptidases / chemistry*
  • Serine Endopeptidases / metabolism*
  • Serine Proteinase Inhibitors / pharmacology
  • Substrate Specificity
  • Temperature
  • Thrombin

Substances

  • Crotalid Venoms
  • Serine Proteinase Inhibitors
  • Fibrinogen
  • Arginine
  • Serine Endopeptidases
  • Thrombin
  • Lysine