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Reduction of folate by dihydrofolate reductase from thermotoga maritima

Loveridge, Edric Joel, Hroch, Lukas, Hughes, Robert L., Williams, Thomas, Davies, Rhidian L., Angelastro, Antonio ORCID:, Luk, Louis Yu Pan ORCID:, Maglia, Giovanni and Allemann, Rudolf Konrad ORCID: 2017. Reduction of folate by dihydrofolate reductase from thermotoga maritima. Biochemistry 56 (13) , pp. 1879-1886. 10.1021/acs.biochem.6b01268

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Mammalian dihydrofolate reductases (DHFRs) catalyze the reduction of folate more efficiently than the equivalent bacterial enzymes do, despite typically having similar efficiencies for the reduction of their natural substrate, dihydrofolate. In contrast, we show here that DHFR from the hyperthermophilic bacterium Thermotoga maritima can catalyze reduction of folate to tetrahydrofolate with an efficiency similar to that of reduction of dihydrofolate under saturating conditions. Nuclear magnetic resonance and mass spectrometry experiments showed no evidence of the production of free dihydrofolate during either the EcDHFR- or TmDHFR-catalyzed reductions of folate, suggesting that both enzymes perform the two reduction steps without release of the partially reduced substrate. Our results imply that the reaction proceeds more efficiently in TmDHFR than in EcDHFR because the more open active site of TmDHFR facilitates protonation of folate. Because T. maritima lives under extreme conditions where tetrahydrofolate is particularly prone to oxidation, this ability to salvage folate may impart an advantage to the bacterium by minimizing the squandering of a valuable cofactor.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Publisher: American Chemical Society Publications
ISSN: 0006-2960
Funders: BBSRC
Date of First Compliant Deposit: 10 April 2017
Date of Acceptance: 20 March 2017
Last Modified: 04 May 2024 01:26

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