Cover image for Vol. 12 Issue 15

Editorial Board Chairs: Karl-Heinz Altmann, Antonello Mai, Rainer Metternich. Editor: David Peralta

Impact Factor: 3.225

ISI Journal Citation Reports © Ranking: 2016: 17/60 (Chemistry Medicinal); 73/256 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

October 13, 2011

VIP: Insights into Matriptase-2 Substrate Binding and Inhibition Mechanisms by Analyzing Active-Site-Mutated Variants

VIP: Insights into Matriptase-2 Substrate Binding and Inhibition Mechanisms by Analyzing Active-Site-Mutated VariantsEva Maurer, Mihiret T. Sisay, Marit Stirnberg, Torsten Steinmetzer, Jürgen Bajorath, Michael Gütschow*

Systemic iron homeostasis is maintained by the interplay of iron absorption, recycling, and storage. The hepatic hormone hepcidin functions as the main regulator of these processes. Its expression is controlled by several proteins, including hemojuvelin. As discovered in the last few years, a transmembrane multidomain serine protease plays a role in the regulation of iron homeostasis. This enzyme, matriptase-2, suppresses the expression of hepcidin by cleavage of hemojuvelin and in this way increases iron plasma levels. Accordingly, the inhibition of matriptase-2 by synthetic inhibitors could be beneficial for the treatment of hemochromatosis. Matriptase-2 is closely related to a further type II transmembrane serine protease, matriptase. The two enzymes share a common domain structure and have high sequence similarity. However, they are expressed in different tissues and participate in different (patho)physiological processes. Matriptase is present on the surface of epithelial cells and is involved in tumor pathogenesis, whereas matriptase-2 is predominantly expressed in the liver.

In a collaborative research project led by Michael Gütschow, researchers at the Pharmaceutical Institute, University of Bonn, the Bonn–Aachen International Center for Information Technology, and the Institute of Pharmaceutical Chemistry, University of Marburg investigated the interaction of matriptase-2 with prototype low-molecular-weight ligands using site-directed mutagenesis, kinetic analysis, and molecular modeling. Relevant amino acids that differ between the active sites of matriptase and matriptase-2, and which are involved in the formation of the binding pockets, were considered for the generation of mutated variants. Residues that enhance or decrease the affinity of peptide ligands for matriptase-2 were identified.

Received July 18, 2011; published online September 14, 2011, DOI: 10.1002/cmdc.201100350.

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