The broad amine scope of pantothenate synthetase enables the synthesis of pharmaceutically relevant amides

Pantothenate synthetase from Escherichia coli (PSE. coli) catalyzes the ATP-dependent condensation of (R)-pantoic acid and beta-alanine to yield (R)-pantothenic acid (vitamin B-5), the biosynthetic precursor to coenzyme A. Herein we show that besides the natural amine substrate beta-alanine, the enzyme accepts a wide range of structurally diverse amines including 3-amino-2-fluoropropionic acid, 4-amino-2-hydroxybutyric acid, 4-amino-3-hydroxybutyric acid, and tryptamine for coupling to the native carboxylic acid substrate (R)-pantoic acid to give amide products with up to >99% conversion. The broad amine scope of PSE. coli enabled the efficient synthesis of pharmaceutically-relevant vitamin B-5 antimetabolites with excellent isolated yield (up to 89%). This biocatalytic amide synthesis strategy may prove to be useful in the quest for new antimicrobials that target coenzyme A biosynthesis and utilisation.

Automated summary

Pantothenate synthetase from Escherichia coli can efficiently synthesize pharmaceutically-relevant vitamin B-5 antimetabolites by accepting a wide range of structurally diverse amines in addition to its natural amine substrate, beta-alanine. This biocatalytic amide synthesis strategy shows promise in the search for new antimicrobials targeting coenzyme A biosynthesis and utilization.