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Chemoenzymatic Assembly of Isotopically Labeled Folates.
- Source :
-
Journal of the American Chemical Society [J Am Chem Soc] 2017 Sep 20; Vol. 139 (37), pp. 13047-13054. Date of Electronic Publication: 2017 Sep 06. - Publication Year :
- 2017
-
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 <superscript>13</superscript> C- and <superscript>15</superscript> N-labeled dihydrofolates (H <subscript>2</subscript> F) from glucose, guanine, and p-aminobenzoyl-l-glutamic acid. This synthesis stands out from previous approaches to produce H <subscript>2</subscript> F 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 H <subscript>2</subscript> F 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.
Details
- Language :
- English
- ISSN :
- 1520-5126
- Volume :
- 139
- Issue :
- 37
- Database :
- MEDLINE
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 28820585
- Full Text :
- https://doi.org/10.1021/jacs.7b06358