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Exploring the reversal of enantioselectivity on a Zinc-dependent Alcohol Dehydrogenase

Alcohol Dehydrogenase (ADH) enzymes catalyse the reversible reduction of prochiral ketones to the corresponding alcohols. These enzymes present two differently shaped active site pockets, which dictate their substrate scope and selectivity. In this study, we computationally evaluate the effect of two commonly reported active site mutations (I86A, and W110T) on a secondary alcohol dehydrogenase from Thermoanaerobacter brockii (TbSADH) through Molecular Dynamics simulations. Our results indicate that the introduced mutations induce dramatic changes on the shape of the active site, but most importantly they impact the substrate-enzyme interactions. We demonstrate that the combination of Molecular Dynamics simulations with the tools POVME and NCIplot correspond to a powerful strategy for rationalising and engineering the stereoselectivity of ADH variants

A.R.R. thanks the Generalitat de Catalunya for PhD fellowship (2015-FI-B-00165), M.A.M.S is grateful to the Spanish MINECO for PhD fellowship (BES-2015-074964). S.O. thanks the Spanish MINECO for project CTQ2014-59212-P, Ramón y Cajal contract (RYC-2014-16846), the European Community for CIG project (PCIG14-GA-2013-630978), and the funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-2015-StG-679001)

Organic and Biomolecular Chemistry, 2017, vol. 15, núm. 19, p. 4122-4129

Royal Society of Chemistry (RSC)

Manager: Ministerio de Economía y Competitividad (Espanya)
Author: Maria Solano, Miguel A.
Romero Rivera, Adrián
Osuna Oliveras, Sílvia
Date: 2017 April 18
Abstract: Alcohol Dehydrogenase (ADH) enzymes catalyse the reversible reduction of prochiral ketones to the corresponding alcohols. These enzymes present two differently shaped active site pockets, which dictate their substrate scope and selectivity. In this study, we computationally evaluate the effect of two commonly reported active site mutations (I86A, and W110T) on a secondary alcohol dehydrogenase from Thermoanaerobacter brockii (TbSADH) through Molecular Dynamics simulations. Our results indicate that the introduced mutations induce dramatic changes on the shape of the active site, but most importantly they impact the substrate-enzyme interactions. We demonstrate that the combination of Molecular Dynamics simulations with the tools POVME and NCIplot correspond to a powerful strategy for rationalising and engineering the stereoselectivity of ADH variants
A.R.R. thanks the Generalitat de Catalunya for PhD fellowship (2015-FI-B-00165), M.A.M.S is grateful to the Spanish MINECO for PhD fellowship (BES-2015-074964). S.O. thanks the Spanish MINECO for project CTQ2014-59212-P, Ramón y Cajal contract (RYC-2014-16846), the European Community for CIG project (PCIG14-GA-2013-630978), and the funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-2015-StG-679001)
Format: application/pdf
ISSN: 1477-0520 (versió paper)
1477-0539 (versió electrònica)
Document access: http://hdl.handle.net/10256/13862
Language: eng
Publisher: Royal Society of Chemistry (RSC)
Collection: MINECO/PE 2015-2017/CTQ2014-59212-P
Reproducció digital del document publicat a: http://dx.doi.org/10.1039/C7OB00482F
Articles publicats (D-Q)
info:eu-repo/grantAgreement/EC/FP7/630978
info:eu-repo/grantAgreement/EC/H2020/679001
Is part of: Organic and Biomolecular Chemistry, 2017, vol. 15, núm. 19, p. 4122-4129
Rights: Attribution-NonCommercial 3.0 Spain
Rights URI: http://creativecommons.org/licenses/by-nc/3.0/es/
Subject: Enzims
Enzymes
Catàlisi
Catalysis
Dinàmica molecular
Molecular dynamics
Title: Exploring the reversal of enantioselectivity on a Zinc-dependent Alcohol Dehydrogenase
Type: info:eu-repo/semantics/article
Repository: DUGiDocs

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