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Discovery of a Phosphonoacetic Acid Derived Natural Product by Pathway Refactoring

Discovery of a Phosphonoacetic Acid Derived Natural Product by Pathway Refactoring

Todd S Freestone, Kou-San Ju, Bin Wang, Huimin Zhao

ACS Synth Biol. 2017 Feb 17;6(2):217-223.

PMID: 28103011

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP4408780	Phosphonoacetic acid		4408-78-0	Price

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