TY - JOUR
T1 - Membrane bound COMT isoform is an interfacial enzyme
T2 - General mechanism and new drug design paradigm
AU - Magarkar, Aniket
AU - Parkkila, Petteri
AU - Viitala, Tapani
AU - Lajunen, Tatu
AU - Mobarak, Edouard
AU - Licari, Giuseppe
AU - Cramariuc, Oana
AU - Vauthey, Eric
AU - Róg, Tomasz
AU - Bunker, Alex
N1 - Funding Information:
Computational resources have been provided by the CSC-IT center for science Ltd (CSC). We wish to thank the Finnish Cultural foundation (A. M.) and the Magnus Ehrenrooth foundation (A. B. and A. M.) for funding. T. V. acknowledges the Academy of Finland for academy research fellow funding (grants #137053 and #294309). Tomasz Róg and Edouard Mobarak wish to thank the Academy of Finland for financial support (Centre of Excellence in Biomembrane Research) and the European Research Council (Advanced Grant project CROWDED-PRO-LIPIDS). T. L. acknowledges Eye and tissue bank foundation #20160004 and Cancer foundation Finland #47-3758-22. G. L. and E. V. acknowledge the Swiss National Science Foundation, Project No. 200020-165890, and the University of Geneva. P. P. acknowledges a grant from the Finnish Pharmaceutical Society.
Publisher Copyright:
© The Royal Society of Chemistry 2018.
PY - 2018/4/11
Y1 - 2018/4/11
N2 - The enzyme catechol-O-methyltransferase (COMT) has water soluble (S-COMT) and membrane associated (MB-COMT), bitopic, isoforms. Of these MB-COMT is a drug target in relation to the treatment of Parkinson's disease. Using a combination of computational and experimental protocols, we have determined the substrate selection mechanism specific to MB-COMT. We show: (1) substrates with preferred affinity for MB-COMT over S-COMT orient in the membrane in a fashion conducive to catalysis from the membrane surface and (2) binding of COMT to its cofactor ADOMET induces conformational change that drives the catalytic surface of the protein to the membrane surface, where the substrates and Mg2+ ions, required for catalysis, are found. Bioinformatics analysis reveals evidence of this mechanism in other proteins, including several existing drug targets. The development of new COMT inhibitors with preferential affinity for MB-COMT over S-COMT is now possible and insight of broader relevance, into the function of bitopic enzymes, is provided.
AB - The enzyme catechol-O-methyltransferase (COMT) has water soluble (S-COMT) and membrane associated (MB-COMT), bitopic, isoforms. Of these MB-COMT is a drug target in relation to the treatment of Parkinson's disease. Using a combination of computational and experimental protocols, we have determined the substrate selection mechanism specific to MB-COMT. We show: (1) substrates with preferred affinity for MB-COMT over S-COMT orient in the membrane in a fashion conducive to catalysis from the membrane surface and (2) binding of COMT to its cofactor ADOMET induces conformational change that drives the catalytic surface of the protein to the membrane surface, where the substrates and Mg2+ ions, required for catalysis, are found. Bioinformatics analysis reveals evidence of this mechanism in other proteins, including several existing drug targets. The development of new COMT inhibitors with preferential affinity for MB-COMT over S-COMT is now possible and insight of broader relevance, into the function of bitopic enzymes, is provided.
UR - http://www.scopus.com/inward/record.url?scp=85044968200&partnerID=8YFLogxK
U2 - 10.1039/c8cc00221e
DO - 10.1039/c8cc00221e
M3 - Article
C2 - 29445781
AN - SCOPUS:85044968200
SN - 1359-7345
VL - 54
SP - 3440
EP - 3443
JO - Chemical Communications
JF - Chemical Communications
IS - 28
ER -