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Different reaction mechanisms for mesophilic and thermophilic dihydrofolate reductases

Loveridge, Edric Joel, Behiry, Enas Mamdouh, Swanwick, Richard S. and Allemann, Rudolf Konrad 2009. Different reaction mechanisms for mesophilic and thermophilic dihydrofolate reductases. Journal of the American Chemical Society 131 (20) , pp. 6926-6927. 10.1021/ja901441k

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Abstract

We report here solvent kinetic isotope effects for two dihydrofolate reductases, namely the monomeric, mesophilic enzyme from E. coli (EcDHFR) and the dimeric, thermophilic enzyme from Thermotoga maritima (TmDHFR). Multiple isotope effects reveal mechanistic differences between the two enzymes. EcDHFR follows a stepwise mechanism in which proton transfer precedes hydride transfer, whereas the two steps are concerted in TmDHFR. At elevated pH, EcDHFR also follows a concerted reaction pathway. TmDHFR at pH 7 behaves more like EcDHFR at elevated pH suggesting that the restricted motions of TmDHFR resulting from dimerization preclude it from modulating the pKa of its substrate as efficiently as EcDHFR. The reduced reaction rates of TmDHFR therefore appear to be a consequence of its quaternary structure, which is required for increased thermostability but which also prevents active modulation of the reactivity of the active site bound substrate observed in EcDHFR.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Cardiff Catalysis Institute (CCI)
Chemistry
Subjects: Q Science > QD Chemistry
Publisher: American Chemical Society
ISSN: 0002-7863
Funders: BBSRC
Last Modified: 31 Oct 2018 11:26
URI: http://orca.cf.ac.uk/id/eprint/6048

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