Journal of the American Chemical Society
Journal of the American Chemical Society
5 years ago

Chemoenzymatic Assembly of Isotopically Labeled Folates

Chemoenzymatic Assembly of Isotopically Labeled Folates
William M. Dawson, Antonio Angelastro, Rudolf K. Allemann, E. Joel Loveridge, Louis Y. P. Luk
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.

Publisher URL: http://dx.doi.org/10.1021/jacs.7b06358

DOI: 10.1021/jacs.7b06358

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