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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

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

Název periodika

Chemical Communications

ISSN

1359-7345

e-ISSN

—

Svazek periodika

54

Číslo periodika v rámci svazku

28

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

4

Strana od-do

3440-3443

Kód UT WoS článku

000429024000003

EID výsledku v databázi Scopus

2-s2.0-85044968200