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

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Membrane bound COMT isoform is an interfacial enzyme : General mechanism and new drug design paradigm. / Magarkar, Aniket; Parkkila, Petteri; Viitala, Tapani; Lajunen, Tatu; Mobarak, Edouard; Licari, Giuseppe; Cramariuc, Oana; Vauthey, Eric; Róg, Tomasz; Bunker, Alex.

In: Chemical Communications, Vol. 54, No. 28, 11.04.2018, p. 3440-3443.

Research output: Contribution to journalArticleScientificpeer-review

Harvard

Magarkar, A, Parkkila, P, Viitala, T, Lajunen, T, Mobarak, E, Licari, G, Cramariuc, O, Vauthey, E, Róg, T & Bunker, A 2018, 'Membrane bound COMT isoform is an interfacial enzyme: General mechanism and new drug design paradigm', Chemical Communications, vol. 54, no. 28, pp. 3440-3443. https://doi.org/10.1039/c8cc00221e

APA

Magarkar, A., Parkkila, P., Viitala, T., Lajunen, T., Mobarak, E., Licari, G., ... Bunker, A. (2018). Membrane bound COMT isoform is an interfacial enzyme: General mechanism and new drug design paradigm. Chemical Communications, 54(28), 3440-3443. https://doi.org/10.1039/c8cc00221e

Vancouver

Magarkar A, Parkkila P, Viitala T, Lajunen T, Mobarak E, Licari G et al. Membrane bound COMT isoform is an interfacial enzyme: General mechanism and new drug design paradigm. Chemical Communications. 2018 Apr 11;54(28):3440-3443. https://doi.org/10.1039/c8cc00221e

Author

Magarkar, Aniket ; Parkkila, Petteri ; Viitala, Tapani ; Lajunen, Tatu ; Mobarak, Edouard ; Licari, Giuseppe ; Cramariuc, Oana ; Vauthey, Eric ; Róg, Tomasz ; Bunker, Alex. / Membrane bound COMT isoform is an interfacial enzyme : General mechanism and new drug design paradigm. In: Chemical Communications. 2018 ; Vol. 54, No. 28. pp. 3440-3443.

Bibtex - Download

@article{c6e06cd42cbc40c0a13c82e95dcb6d12,
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",
year = "2018",
month = "4",
day = "11",
doi = "10.1039/c8cc00221e",
language = "English",
volume = "54",
pages = "3440--3443",
journal = "Chemical Communications",
issn = "1359-7345",
publisher = "ROYAL SOC CHEMISTRY",
number = "28",

}

RIS (suitable for import to EndNote) - Download

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

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.

U2 - 10.1039/c8cc00221e

DO - 10.1039/c8cc00221e

M3 - Article

VL - 54

SP - 3440

EP - 3443

JO - Chemical Communications

JF - Chemical Communications

SN - 1359-7345

IS - 28

ER -