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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

IMPACT FACTOR 2018: 3.014
5-year IMPACT FACTOR: 3.162

CiteScore 2018: 3.09

SCImago Journal Rank (SJR) 2018: 1.482
Source Normalized Impact per Paper (SNIP) 2018: 0.820

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Volume 400, Issue 6


Metalloprotease inhibitor profiles of human ADAM8 in vitro and in cell-based assays

Uwe Schlomann / Kristina Dorzweiler / Elisa Nuti / Tiziano Tuccinardi / Armando Rossello / Jörg W. BartschORCID iD: https://orcid.org/0000-0002-2773-3357
Published Online: 2019-03-04 | DOI: https://doi.org/10.1515/hsz-2018-0396


ADAM8 as a membrane-anchored metalloproteinase-disintegrin is upregulated under pathological conditions such as inflammation and cancer. As active sheddase, ADAM8 can cleave several membrane proteins, among them the low-affinity receptor FcεRII CD23. Hydroxamate-based inhibitors are routinely used to define relevant proteinases involved in ectodomain shedding of membrane proteins. However, for ADAM proteinases, common hydroxamates have variable profiles in their inhibition properties, commonly known for ADAM proteinases 9, 10 and 17. Here, we determined the inhibitor profile of human ADAM8 for eight ADAM/MMP inhibitors by in vitro assays using recombinant ADAM8 as well as the in vivo inhibition in cell-based assays using HEK293 cells to monitor the release of soluble CD23 by ADAM8. ADAM8 activity is inhibited by BB94 (Batimastat), GW280264, FC387 and FC143 (two ADAM17 inhibitors), made weaker by GM6001, TAPI2 and BB2516 (Marimastat), while no inhibition was observed for GI254023, an ADAM10 specific inhibitor. Modeling of inhibitor FC143 bound to the catalytic sites of ADAM8 and ADAM17 reveals similar geometries in the pharmacophoric regions of both proteinases, which is different in ADAM10 due to replacement in the S1 position of T300 (ADAM8) and T347 (ADAM17) by V327 (ADAM10). We conclude that ADAM8 inhibitors require maximum selectivity over ADAM17 to achieve specific ADAM8 inhibition.

This article offers supplementary material which is provided at the end of the article.

Keywords: ADAM8; cell-based assay; ectodomain cleavage; hydroxamates; low-affinity IgE receptor FcεRII (CD23); recombinant protein


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About the article

Received: 2018-10-10

Accepted: 2018-12-19

Published Online: 2019-03-04

Published in Print: 2019-06-26

Funding Source: Deutsche Forschungsgemeinschaft

Award identifier / Grant number: BA1606/3-1

This work was supported by the Deutsche Forschungsgemeinschaft (Funder Id: 10.13039/501100001659, BA1606/3-1 to J.W.B. and U.S.) and by the University of Pisa (PRA_2018_20). We thank Sarah Koch (Marburg) for help with enzyme assays, Luciana Marinelli and Valeria La Pietra (Naples) for providing us with the docking model ADAM17/FC143, Muriel Bartsch for help with IC50 calculations, and Vincent Dive (Gif-sur-Yvette, France) for helpful discussions on the ADAM8 structure.

Citation Information: Biological Chemistry, Volume 400, Issue 6, Pages 801–810, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2018-0396.

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