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Effect of dimerization on dihydrofolate reductase catalysis

Guo, Jiannan, Loveridge, Edric Joel, Luk, Louis Yu Pan ORCID: https://orcid.org/0000-0002-7864-6261 and Allemann, Rudolf Konrad ORCID: https://orcid.org/0000-0002-1323-8830 2013. Effect of dimerization on dihydrofolate reductase catalysis. Biochemistry 52 (22) , pp. 3881-3887. 10.1021/bi4005073

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Abstract

Dihydrofolate reductase (DHFR) from the hyperthermophile Thermotoga maritima (TmDHFR) forms a very stable homodimer, while DHFRs from other organisms are monomers. We investigated the effect of dimerization on DHFR catalysis by preparing a dimeric variant, Xet-3, of DHFR from Escherichia coli (EcDHFR). Introducing residues located at the TmDHFR dimer interface into EcDHFR increases the melting temperature to 60 °C, approximately 9 °C higher than that measured for EcDHFR. The steady-state and pre-steady-state rate constants measured for Xet-3 were similar to those of dimeric TmDHFR but significantly lower than those of the parent EcDHFR. This reduction in the degree of catalytic competence is likely a consequence of the loss of flexibility of catalytically important loop regions of EcDHFR on dimerization and a compromise of the electrostatic environment of the active site. In contrast, the reduced catalytic ability of TmDHFR relative to that of EcDHFR is not simply a consequence of reduced loop flexibility in the dimeric enzyme. Our studies demonstrate that EcDHFR is not a good model for understanding the properties of other DHFRs, including TmDHFR.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Cardiff Catalysis Institute (CCI)
Chemistry
Subjects: Q Science > QD Chemistry
Publisher: American Chemical Society
ISSN: 0006-2960
Funders: BBSRC
Last Modified: 25 Oct 2022 09:46
URI: https://orca.cardiff.ac.uk/id/eprint/59956

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