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Use of the dehydrophos biosynthetic enzymes to prepare antimicrobial analogs of alaphosphin

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Abstract

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 (Ile, Ala, Val, Met, norvaline, and norleucine). DhpH-C accepted these aminoacyl-tRNA derivatives and condensed the amino acid with L-Ala(P) to form the corresponding phosphonodipeptides. A subset of these peptides displayed antimicrobial activities demonstrating that the enzyme is a versatile biocatalyst for the preparation of antimicrobial peptides. We also investigated another enzyme from the dehydrophos biosynthetic pathway, the 2-oxoglutarate dependent enzyme DhpA. This enzyme oxidizes 2-hydroxyethylphosphonate to 1,2-dihydroxyethylphosphonate en route to L-Ala(P), but longer incubation results in overoxidation to 1-oxo-2-hydroxyethylphosphonate. This α-ketophosphonate was converted by the pyridoxal phosphate dependent enzyme DhpD into L-Ser(P). Thus, the dehydrophos biosynthetic enzymes can generate not only L-Ala(P) but also L-Ser(P).

Graphical abstract: Use of the dehydrophos biosynthetic enzymes to prepare antimicrobial analogs of alaphosphin

  • This article is part of the themed collection: Biosynthesis
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Publication details

The article was received on 16 Nov 2018, accepted on 20 Dec 2018 and first published on 20 Dec 2018


Article type: Paper
DOI: 10.1039/C8OB02860E
Citation: Org. Biomol. Chem., 2019, Advance Article
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    Use of the dehydrophos biosynthetic enzymes to prepare antimicrobial analogs of alaphosphin

    D. J. Bougioukou, C. P. Ting, S. C. Peck, S. Mukherjee and W. A. van der Donk, Org. Biomol. Chem., 2019, Advance Article , DOI: 10.1039/C8OB02860E

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