title: Discovery of a Phosphonoacetic Acid Derived Natural Product by Pathway Refactoring.
abstract: The activation of silent natural product gene clusters is a synthetic biology problem of great interest. As the rate at which gene clusters are identified outpaces the discovery rate of new molecules, this unknown chemical space is rapidly growing, as too are the rewards for developing technologies to exploit it. One class of natural products that has been underrepresented is phosphonic acids, which have important medical and agricultural uses. Hundreds of phosphonic acid biosynthetic gene clusters have been identified encoding for unknown molecules. Although methods exist to elicit secondary metabolite gene clusters in native hosts, they require the strain to be amenable to genetic manipulation. One method to circumvent this is pathway refactoring, which we implemented in an effort to discover new phosphonic acids from a gene cluster from Streptomyces sp. strain NRRL F-525. By reengineering this cluster for expression in the production host Streptomyces lividans, utility of refactoring is demonstrated with the isolation of a novel phosphonic acid, O-phosphonoacetic acid serine, and the characterization of its biosynthesis. In addition, a new biosynthetic branch point is identified with a phosphonoacetaldehyde dehydrogenase, which was used to identify additional phosphonic acid gene clusters that share phosphonoacetic acid as an intermediate.
authors.affiliation: Department of Chemical and Biomolecular Engineering, ‡Carl R. Woese Institute for Genomic Biology, §Departments of Biochemistry, Bioengineering, and Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Todd S
authors.initials: TS
authors.lastname: Freestone
authors.affiliation: Department of Chemical and Biomolecular Engineering, ‡Carl R. Woese Institute for Genomic Biology, §Departments of Biochemistry, Bioengineering, and Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Kou-San
authors.initials: KS
authors.lastname: Ju
authors.affiliation: Department of Chemical and Biomolecular Engineering, ‡Carl R. Woese Institute for Genomic Biology, §Departments of Biochemistry, Bioengineering, and Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Chemical and Biomolecular Engineering, ‡Carl R. Woese Institute for Genomic Biology, §Departments of Biochemistry, Bioengineering, and Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Huimin
authors.identifier: 0000-0002-9069-6739
authors.initials: H
authors.lastname: Zhao
mesh_terms: D001688:Biological Products / Q000378:metabolism*; D006867:Hydrolases / Q000378:metabolism; D005810:Multigene Family / Q000235:genetics; D010746:Phosphonoacetic Acid / Q000378:metabolism*; D010757:Phosphorous Acids / Q000378:metabolism; D013302:Streptomyces / Q000254:growth & development; D058615:Synthetic Biology
chemical_list: D001688:Biological Products; D010757:Phosphorous Acids; C570063:phosphonic acid; D006867:Hydrolases; C023920:phosphonoacetaldehyde hydrolase; D010746:Phosphonoacetic Acid
keywords: natural products; pathway refactoring; phosphonic acids; phosphonoacetic acid