biostudies-literatureBougioukou DJNCRR NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS822-829https://www.ebi.ac.uk/biostudies/studies/S-EPMC6344287biostudies-literatureUnknown17(4)The C-terminal domain of the dehydrophos biosynthetic enzyme DhpH (DhpH-C) catalyzes the condensation of Leu-tRNALeu with (R)-1-aminoethylphosphonate, the aminophosphonate analog of alanine called Ala(P). The product of this reaction, Leu-Ala(P), is a phosphonodipeptide, a class of compounds that have previously been investigated for use as clinical antibiotics. In this study, we show that DhpH-C is highly substrate tolerant and can condense various aminophosphonates (Gly(P), Ser(P), Val(P), 1-amino-propylphosphonate, and phenylglycine(P)) to Leu. Moreover, the enzyme is also tolerant with respect to the amino acid attached to tRNALeu. Using a mutant of leucyl tRNA synthetase that is deficient in its proofreading ability allowed the preparation of a series of aminoacyl-tRNALeu derivatives Organic & biomolecular chemistryUse of the dehydrophos biosynthetic enzymes to prepare antimicrobial analogs of alaphosphin.PMC6344287S10-RR028833S10 RR028833F32 GM129944P01 GM077596GM 077596Bougioukou DJPeck SCMukherjee STing CPvan der Donk WAfalseUse of the dehydrophos biosynthetic enzymes to prepare antimicrobial analogs of alaphosphin.The C-terminal domain of the dehydrophos biosynthetic enzyme DhpH (DhpH-C) catalyzes the condensation of Leu-tRNALeu with (R)-1-aminoethylphosphonate, the aminophosphonate analog of alanine called Ala(P). The product of this reaction, Leu-Ala(P), is a phosphonodipeptide, a class of compounds that have previously been investigated for use as clinical antibiotics. In this study, we show that DhpH-C is highly substrate tolerant and can condense various aminophosphonates (Gly(P), Ser(P), Val(P), 1-amino-propylphosphonate, and phenylglycine(P)) to Leu. Moreover, the enzyme is also tolerant with respect to the amino acid attached to tRNALeu. Using a mutant of leucyl tRNA synthetase that is deficient in its proofreading ability allowed the preparation of a series of aminoacyl-tRNALeu derivatives 2019-01-01T00:00:00Z2019 Jan2025-04-04T02:39:35.86Z2020-10-29T12:52:45ZS-EPMC63442873060810810.1039/c8ob02860e