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Cathepsins X and B display distinct activity profiles that can be exploited for inhibitor design

Academic Article
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Overview

authors

  • Menard, R.
  • Therrien, C.
  • Lachance, P.
  • Sulea, T.
  • Qi, H. T.
  • Alvarez-Hernandez, A.
  • Roush, William

publication date

  • May 2001

journal

  • Biological Chemistry  Journal

abstract

  • The carboxypeptidase and endopeptidase activities of cathepsins X and B, as well as their inhibition by E-64 derivatives, have been investigated in detail and compared. The results clearly demonstrate that cathepsins X and B do not share similar activity profiles against substrates and inhibitors. Using quenched fluorogenic substrates, we show that cathepsin X preferentially cleaves substrates through a monopeptidyl carboxypeptidase pathway, while cathepsin B displays a preference for the dipeptidyl pathway. The preference for one or the other pathway is about the same for both enzymes, i. e. approximately 2 orders of magnitude. Cleavage of a C-terminal dipeptide of a substrate by cathepsin X can be observed under conditions that preclude efficient monopeptidyl carboxypeptidase activity. In addition, an inhibitor designed to exploit the unique structural features responsible for the carboxypeptidase activity of cathepsin X has been synthesized and tested against cathepsins X, B and L. Although of moderate potency, this E-64 derivative is the first reported example of a cathepsin X-specific inhibitor. By comparison, CA074 was found to inactivate cathepsin B at least 34000-fold more efficiently than cathepsin X.

subject areas

  • Cathepsin B
  • Cathepsin K
  • Cathepsins
  • Cysteine Endopeptidases
  • Cysteine Proteinase Inhibitors
  • Drug Design
  • Enzyme Inhibitors
  • Exopeptidases
  • Fluorescent Dyes
  • Humans
  • Leucine
  • Models, Chemical
  • Substrate Specificity
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Research

keywords

  • carboxypeptidase
  • cathepsin B
  • cathepsin X
  • cysteine protease
  • inhibitor
  • specificity
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Identity

International Standard Serial Number (ISSN)

  • 1431-6730

Digital Object Identifier (DOI)

  • 10.1515/bc.2001.102

PubMed ID

  • 11517939
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Additional Document Info

start page

  • 839

end page

  • 845

volume

  • 382

issue

  • 5

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