Membrane bound COMT isoform is an interfacial enzyme: general mechanism and new drug design paradigm

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00490133" target="_blank" >RIV/61388963:_____/18:00490133 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1039/c8cc00221e" target="_blank" >http://dx.doi.org/10.1039/c8cc00221e</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/c8cc00221e" target="_blank" >10.1039/c8cc00221e</a>

Result language

angličtina

Original language name

Membrane bound COMT isoform is an interfacial enzyme: general mechanism and new drug design paradigm

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10403 - Physical chemistry

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Chemical Communications

ISSN

1359-7345

e-ISSN

—

Volume of the periodical

54

Issue of the periodical within the volume

28

Country of publishing house

GB - UNITED KINGDOM

Number of pages

4

Pages from-to

3440-3443

UT code for WoS article

000429024000003

EID of the result in the Scopus database

2-s2.0-85044968200