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

Aniket Magarkar; Petteri Parkkila; Tapani Viitala; Tatu Lajunen; Edouard Mobarak; Giuseppe Licari; Oana Cramariuc; Eric Vauthey; Tomasz Róg; Alex Bunker

doi:10.1039/c8cc00221e

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

Aniket Magarkar
, Petteri Parkkila
, Tapani Viitala
, Tatu Lajunen
, Edouard Mobarak
, Giuseppe Licari
, Oana Cramariuc
, Eric Vauthey
, Tomasz Róg
, Alex Bunker^*

^*Tämän työn vastaava kirjoittaja

Tutkimustuotos: Lehtiartikkeli › Artikkeli › Tieteellinen › vertaisarvioitu

20 Sitaatiot (Scopus)

Abstrakti

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.

Alkuperäiskieli	Englanti
Sivut	3440-3443
Sivumäärä	4
Julkaisu	Chemical Communications
Vuosikerta	54
Numero	28
DOI - pysyväislinkit	https://doi.org/10.1039/c8cc00221e
Tila	Julkaistu - 11 huhtik. 2018
Julkaistu ulkoisesti	Kyllä
OKM-julkaisutyyppi	A1 Julkaistu artikkeli, soviteltu

Rahoitus

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.

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10.1039/c8cc00221e

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@article{743900954d8d47509723af4684d52b0d,

title = "Membrane bound COMT isoform is an interfacial enzyme: General mechanism and new drug design paradigm",

abstract = "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.",

author = "Aniket Magarkar and Petteri Parkkila and Tapani Viitala and Tatu Lajunen and Edouard Mobarak and Giuseppe Licari and Oana Cramariuc and Eric Vauthey and Tomasz R{\'o}g and Alex Bunker",

note = "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 R{\'o}g 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: {\textcopyright} The Royal Society of Chemistry 2018.",

year = "2018",

month = apr,

day = "11",

doi = "10.1039/c8cc00221e",

language = "English",

volume = "54",

pages = "3440--3443",

journal = "Chemical Communications",

issn = "1359-7345",

publisher = "Royal Society of Chemistry",

number = "28",

}

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 - https://www.scopus.com/pages/publications/85044968200

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 -

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

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