The Mechanism of a Bacterial Plasminogen Activator Intermediate between Streptokinase and Staphylokinase

Irina Y. Sazonova, Aiilyan K. Houng, Shakeel A. Chowdhry, Brian R. Robinson, Lizbeth Hedstrom, Guy L. Reed

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

The therapeutic properties of plasminogen activators are dictated by their mechanism of action. Unlike staphylokinase, a single domain protein, streptokinase, a 3-domain (α, β, and γ) molecule, nonproteolytically activates human (h)-plasminogen and protects plasmin from inactivation by α2-antiplasmin. Because a streptokinase-like mechanism was hypothesized to require the streptokinase γ-domain, we examined the mechanism of action of a novel two-domain (α,β) Streptococcus uberis plasminogen activator (SUPA). Under conditions that quench trace plasmin, SUPA nonproteolytically generated an active site in bovine (b)-plasminogen. SUPA also competitively inhibited the inactivation of plasmin by α2-antiplasmin. Still, the lag phase in active site generation and plasminogen activation by SUPA was at least 5-fold longer than that of streptokinase. Recombinant streptokinase γ-domain bound to the b-plasminogen·SUPA complex and significantly reduced these lag phases. The SUPA-b·plasmin complex activated b-plasminogen with kinetic parameters comparable to those of streptokinase for h-plasminogen. The SUPA-b·plasmin complex also activated h-plasminogen but with a lower kcat (25-fold) and kcat/Km (7.9-fold) than SK. We conclude that a γ-domain is not required for a streptokinase-like activation of b-plasminogen. However, the streptokinase γ-domain enhances the rates of active site formation in b-plasminogen and this enhancing effect may be required for efficient activation of plasminogen from other species.

Original languageEnglish (US)
Pages (from-to)12609-12613
Number of pages5
JournalJournal of Biological Chemistry
Volume276
Issue number16
DOIs
StatePublished - Apr 20 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Sazonova, I. Y., Houng, A. K., Chowdhry, S. A., Robinson, B. R., Hedstrom, L., & Reed, G. L. (2001). The Mechanism of a Bacterial Plasminogen Activator Intermediate between Streptokinase and Staphylokinase. Journal of Biological Chemistry, 276(16), 12609-12613. https://doi.org/10.1074/jbc.M009265200