Chemoenzymatic Assembly of Isotopically Labeled Folates

Antonio Angelastro, William M. Dawson, Louis Y.P. Luk, E. Joel Loveridge, Rudolf K. Allemann*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)
122 Downloads (Pure)

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 chemoenzymatic 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 a 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 reaction catalyzed by the drug target dihydrofolate reductase and established that protonation at N5 of H2F and hydride transfer to C6 occur in a stepwise mechanism. This chemoenzymatic 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.

Original languageEnglish
Pages (from-to)13047-13054
Number of pages8
JournalJournal of the American Chemical Society
Volume139
Issue number37
Early online date18 Aug 2017
DOIs
Publication statusPublished - 20 Sep 2017

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