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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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Volume 394, Issue 9


Cathepsin K: a unique collagenolytic cysteine peptidase

Marko Novinec
  • Corresponding author
  • Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia
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  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Brigita Lenarčič
  • Corresponding author
  • Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia
  • Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia
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Published Online: 2013-04-27 | DOI: https://doi.org/10.1515/hsz-2013-0134


Cathepsin K has emerged as a promising target for the treatment of osteoporosis in recent years. Initially identified as a papain-like cysteine peptidase expressed in high levels in osteoclasts, the important role of this enzyme in bone metabolism was highlighted by the finding that mutations in the CTSK gene cause the rare recessive disorder pycnodysostosis, which is characterized by severe bone anomalies. At the molecular level, the physiological role of cathepsin K is reflected by its unique cleavage pattern of type I collagen molecules, which is fundamentally different from that of other endogenous collagenases. Several cathepsin K inhibitors have been developed to reduce the excessive bone matrix degradation associated with osteoporosis, with the frontrunner odanacatib about to successfully conclude Phase 3 clinical trials. Apart from osteoclasts, cathepsin K is expressed in different cell types throughout the body and is involved in processes of adipogenesis, thyroxine liberation and peptide hormone regulation. Elevated activity of cathepsin K has been associated with arthritis, atherosclerosis, obesity, schizophrenia, and tumor metastasis. Accordingly, its activity is tightly regulated via multiple mechanisms, including competitive inhibition by endogenous macromolecular inhibitors and allosteric regulation by glycosaminoglycans. This review provides a state-of-the-art description of the activity of cathepsin K at the molecular level, its biological functions and the mechanisms involved in its regulation.

Keywords: allostery; collagen; cysteine peptidase; glycosaminoglycan; osteoporosis; proteolysis


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About the article

Marko Novinec

Marko Novinec did his PhD studies at the Jožef Stefan Institute, Ljubljana, Slovenia and received a PhD in Biomedicine from the University of Ljubljana, Slovenia in 2008. He continued his training as a Postdoc in the group of Prof. Antonio Baici at the University of Zürich, Switzerland, where he investigated the mechanisms of allosteric regulation in cysteine peptidases. Since 2013, he is Assistant Professor of Biochemistry at the Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. His research focuses on the structure-function-evolution relationships in enzymes.

Brigita Lenarčič

Brigita Lenarčič holds a BSc in Pharmacy and a PhD in Chemistry from the University of Ljubljana, Slovenia. She was a guest scientist at the University of Notre Dame, Indiana, USA and Sincrotrone Trieste, Italy. She works as a senior researcher at the Jožef Stefan Institute, Ljubljana, Slovenia. Since 2006 she is Professor of Biochemistry and Head of the Chair of Biochemistry at the Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. Her research focuses on the structure-function relationships in extracellular matrix proteins and regulation of peptidase activity.

Corresponding authors: Marko Novinec, Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia; and Brigita Lenarčič, Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia; and Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia

Received: 2013-02-07

Accepted: 2013-04-24

Published Online: 2013-04-27

Published in Print: 2013-09-01

Citation Information: Biological Chemistry, Volume 394, Issue 9, Pages 1163–1179, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2013-0134.

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