title: Nature's combinatorial biosynthesis and recently engineered production of nucleoside antibiotics in Streptomyces.
abstract: Modified nucleosides produced by Streptomyces and related actinomycetes are widely used in agriculture and medicine as antibacterial, antifungal, anticancer and antiviral agents. These specialized small-molecule metabolites are biosynthesized by complex enzymatic machineries encoded within gene clusters in the genome. The past decade has witnessed a burst of reports defining the key metabolic processes involved in the biosynthesis of several distinct families of nucleoside antibiotics. Furthermore, genome sequencing of various Streptomyces species has dramatically increased over recent years. Potential biosynthetic gene clusters for novel nucleoside antibiotics are now apparent by analysis of these genomes. Here we revisit strategies for production improvement of nucleoside antibiotics that have defined mechanisms of action, and are in clinical or agricultural use. We summarize the progress for genetically manipulating biosynthetic pathways for structural diversification of nucleoside antibiotics. Microorganism-based biosynthetic examples are provided and organized under genetic principles and metabolic engineering guidelines. We show perspectives on the future of combinatorial biosynthesis, and present a working model for discovery of novel nucleoside natural products in Streptomyces.
authors.affiliation: Pennsylvania Biotechnology Center, Revive Genomics Inc., 3805 Old Easton Rd, Doylestown, PA, 18902, USA. schen169@hotmail.com.
authors.forename: Shawn
authors.identifier: http://orcid.org/0000-0002-6678-3293
authors.initials: S
authors.lastname: Chen
authors.affiliation: Pennsylvania Biotechnology Center, Revive Genomics Inc., 3805 Old Easton Rd, Doylestown, PA, 18902, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Kinney
authors.affiliation: Division of Bioorganic, Medicinal, & Computational Chemistry, University of Kentucky College of Pharmacy, 789 S. Limestone St, Lexington, KY, 40536, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Van Lanen
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics; D053898:Biosynthetic Pathways; D055808:Drug Discovery; D005818:Genetic Engineering / Q000379:methods*; D016680:Genome, Bacterial; D008826:Microbial Sensitivity Tests; D005810:Multigene Family; D009705:Nucleosides / Q000096:biosynthesis* / Q000494:pharmacology; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009705:Nucleosides
keywords: Gene clusters; Metabolic engineering; Natural product biosynthesis; Nucleoside antibiotics; Streptomyces