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Chemoenzymatic assembly of isotopically labeled folates

Angelastro, Antonio, Dawson, William M., Luk, Louis Y. P., Loveridge, Edric Joel and Allemann, Rudolf K. 2017. Chemoenzymatic assembly of isotopically labeled folates. Journal of the American Chemical Society 139 (37) , pp. 13047-13054. 10.1021/jacs.7b06358

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Abstract

Pterin-containing natural products have diverse functions in life but an efficient and easy scheme for their in vitro synthesis is not available. Here, we report a chemo-enzymatic 14-step, one-pot synthesis that can be used to generate 13C- and 15N-labeled dihydrofolates (H2F) from glucose, guanine and p-aminobenzoyl-L-glutamic acid. This synthesis stands out from previous approaches to produce H2F in that the average yield of each step is >91% and it requires only one single purification step. The use of a one-pot reaction allowed us to overcome potential problems with individual steps during the synthesis. The availability of labeled dihydrofolates allowed the measurement of heavy atom isotope effects for the reactions catalyzed by the drug target dihydrofolate reductase and established that protonation at the N5 position of H2F and hydride transfer to the C4 position occur in a stepwise mechanism. This chemo-enzymatic pterin synthesis can be applied to the efficient production of other folates and a range of other natural compounds with applications in nutritional, medical and cell biological research.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Chemistry
Publisher: American Chemical Society
ISSN: 0002-7863
Funders: Biotechnology and Biological Sciences Research Council (BBSRC)
Date of First Compliant Deposit: 27 September 2017
Date of Acceptance: 18 July 2017
Last Modified: 28 Nov 2018 21:30
URI: http://orca.cf.ac.uk/id/eprint/105022

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