title: Disruption of an aromatase/cyclase from the oxytetracycline gene cluster of Streptomyces rimosus results in production of novel polyketides with shorter chain lengths.
abstract: Oxytetracycline is a polyketide antibiotic made by Streptomyces rimosus. From DNA sequencing, the gene product of otcD1 is deduced to function as a bifunctional cyclase/aromatase involved in ring closure of the polyketide backbone. Although otcD1 is contiguous with the ketoreductase gene, they are located an unusually large distance from the genes encoding the "minimal polyketide synthase" of the oxytetracycline gene cluster. A recombinant, disrupted in the genomic copy of otcD1, made four novel polyketides, all of shorter chain length (by up to 10 carbons) than oxytetracycline. All four novel structures contained the unusual carboxamido group, typical of oxytetracycline. This implies that the carboxamido group is present at the start of biosynthesis of oxytetracycline, a topic that has been debated in the literature. Loss of the cyclase protein has a profound influence on the length of polyketide chain assembled, implying that OtcD1 plays a greater role in the overall integrity of the quaternary structure of the polyketide complex than hitherto imagined.
authors.affiliation: Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, Scotland G1 1XW, United Kingdom.
authors.forename: H
authors.initials: H
authors.lastname: Petkovic
authors.forename: A
authors.initials: A
authors.lastname: Thamchaipenet
authors.forename: L H
authors.initials: LH
authors.lastname: Zhou
authors.forename: D
authors.initials: D
authors.lastname: Hranueli
authors.forename: P
authors.initials: P
authors.lastname: Raspor
authors.forename: P G
authors.initials: PG
authors.lastname: Waterman
authors.forename: I S
authors.initials: IS
authors.lastname: Hunter
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry; D001141:Aromatase / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D005798:Genes, Bacterial / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics*; D010118:Oxytetracycline / Q000031:analogs & derivatives / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000378:metabolism; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; C402298:otcD1 protein, Streptomyces rimosus; D001141:Aromatase; D010118:Oxytetracycline