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Effect of dimerization on dihydrofolate reductase catalysis

Guo, Jiannan, Loveridge, Edric Joel, Luk, Louis Yu Pan and Allemann, Rudolf Konrad 2013. Effect of dimerization on dihydrofolate reductase catalysis. Biochemistry 52 (22) , pp. 3881-3887. 10.1021/bi4005073

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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)
Subjects: Q Science > QD Chemistry
Publisher: American Chemical Society
ISSN: 0006-2960
Funders: BBSRC
Last Modified: 05 Jun 2017 04:28

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