title: Insights into the pamamycin biosynthesis.
abstract: Pamamycins are macrodiolides of polyketide origin with antibacterial activities. Their biosynthesis has been proposed to utilize succinate as a building block. However, the mechanism of succinate incorporation into a polyketide was unclear. Here, we report identification of a pamamycin biosynthesis gene cluster by aligning genomes of two pamamycin-producing strains. This unique cluster contains polyketide synthase (PKS) genes encoding seven discrete ketosynthase (KS) enzymes and one acyl-carrier protein (ACP)-encoding gene. A cosmid containing the entire set of genes required for pamamycin biosynthesis was successfully expressed in a heterologous host. Genetic and biochemical studies allowed complete delineation of pamamycin biosynthesis. The pathway proceeds through 3-oxoadipyl-CoA, a key intermediate in the primary metabolism of the degradation of aromatic compounds. 3-Oxoadipyl-CoA could be used as an extender unit in polyketide assembly to facilitate the incorporation of succinate.
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Actinobacteria Metabolic Engineering Group, UdS Campus, C2 3, 66123 Saarbrücken (Germany).
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Rebets
authors.forename: Elke
authors.initials: E
authors.lastname: Brötz
authors.forename: Niko
authors.initials: N
authors.lastname: Manderscheid
authors.forename: Bogdan
authors.initials: B
authors.lastname: Tokovenko
authors.forename: Maksym
authors.initials: M
authors.lastname: Myronovskyi
authors.forename: Peter
authors.initials: P
authors.lastname: Metz
authors.forename: Lutz
authors.initials: L
authors.lastname: Petzke
authors.forename: Andriy
authors.initials: A
authors.lastname: Luzhetskyy
mesh_terms: D000213:Acyl Carrier Protein / Q000235:genetics / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D053898:Biosynthetic Pathways; D018942:Macrolides / Q000378:metabolism*; D005810:Multigene Family; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*
chemical_list: D000213:Acyl Carrier Protein; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D018942:Macrolides; C024500:pamamycin; D048630:Polyketide Synthases
keywords: Streptomyces; biosynthesis; polyketide synthase; polyketides; succinate