Investigations into the biosynthesis and mode of action of the phosphonate antibiotic dehydrophos
type: CreativeWork
description: Dehydrophos is a vinyl phosphonate tripeptide produced by Streptomyces luridus with demonstrated broad spectrum antibiotic activity. Dehydrophos antibiotic activity was determined to be dependent on uptake into the cell via non-specific oligopeptide permeases, followed by aminopeptidase catalyzed digestion. Bioactivity was abolished in Salmonella quadruple mutants lacking peptidases PepA, PepB, PepD, and PepN. However, reintroduction of any one of these peptidases resulted in restored bioactivity. Following peptidase action the released C-terminal portion of dehydrophos, a phosphonate analogue of dehydroalanine, undergoes a tautomeric rearrangement followed by hydrolysis to yield methyl acetylphosphonate, a structural analogue of pyruvate, and known inhibitor of pyruvate dehydrogenase and pyruvate oxidase. To identify genes necessary for the biosynthesis of this unusual compound we screened a fosmid library of S. luridus for the presence of the phosphoenolpyruvate mutase gene, which is required for biosynthesis of most phosphonates. Integration of one such fosmid clone into the chromosome of Streptomyces lividans led to heterologous production of dehydrophos. Deletion analysis of this clone allowed identification of the minimal contiguous dehydrophos cluster, which contained 17 open reading frames (ORFs). Bioinformatic analyses of these ORFs are consistent with a proposed biosynthetic pathway that generates dehydrophos from phosphoenolpyruvate. The early steps of this pathway are supported by analysis of intermediates accumulated by blocked mutants and in vitro biochemical experiments.
abstract: Dehydrophos is a vinyl phosphonate tripeptide produced by Streptomyces luridus with demonstrated broad spectrum antibiotic activity. Dehydrophos antibiotic activity was determined to be dependent on uptake into the cell via non-specific oligopeptide permeases, followed by aminopeptidase catalyzed digestion. Bioactivity was abolished in Salmonella quadruple mutants lacking peptidases PepA, PepB, PepD, and PepN. However, reintroduction of any one of these peptidases resulted in restored bioactivity. Following peptidase action the released C-terminal portion of dehydrophos, a phosphonate analogue of dehydroalanine, undergoes a tautomeric rearrangement followed by hydrolysis to yield methyl acetylphosphonate, a structural analogue of pyruvate, and known inhibitor of pyruvate dehydrogenase and pyruvate oxidase. To identify genes necessary for the biosynthesis of this unusual compound we screened a fosmid library of S. luridus for the presence of the phosphoenolpyruvate mutase gene, which is required for biosynthesis of most phosphonates. Integration of one such fosmid clone into the chromosome of Streptomyces lividans led to heterologous production of dehydrophos. Deletion analysis of this clone allowed identification of the minimal contiguous dehydrophos cluster, which contained 17 open reading frames (ORFs). Bioinformatic analyses of these ORFs are consistent with a proposed biosynthetic pathway that generates dehydrophos from phosphoenolpyruvate. The early steps of this pathway are supported by analysis of intermediates accumulated by blocked mutants and in vitro biochemical experiments.
author: Circello, Benjamin T.
language: en
keywords: phosphonate, antibiotic, Streptomyces, drug discovery
date published: 2011-01-21T22:47:11Z
date modified: 2026-07-22T22:25:11Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/18576