Identification of the tirandamycin biosynthetic gene cluster from Streptomyces sp. 307-9.
The structurally intriguing bicyclic ketal moiety of tirandamycin is common to several acyl-tetramic acid antibiotics, and is a key determinant of biological activity. We have identified the tirandamycin biosynthetic gene cluster from the environmental marine isolate Streptomyces sp. 307-9, thus providing the first genetic insight into the biosynthesis of this natural product scaffold. Sequence analysis revealed a hybrid polyketide synthase-nonribosomal peptide synthetase gene cluster with a colinear domain organization, which is entirely consistent with the core structure of the tirandamycins. We also identified genes within the cluster that encode candidate tailoring enzymes for elaboration and modification of the bicyclic ketal system. Disruption of tamI, which encodes a presumed cytochrome P450, led to a mutant strain deficient in production of late stage tirandamycins that instead accumulated tirandamycin C, an intermediate devoid of any post assembly-line oxidative modifications.
Carlson
Jacob C
JC
Life Sciences Institute and Departments of Medicinal Chemistry, Microbiology, Immunology and Chemistry, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI, USA.
Fortman
J L
JL
Anzai
Yojiro
Y
Li
Shengying
S
Burr
Douglas A
DA
Sherman
David H
DH
D000595:Amino Acid Sequence; D000617:Aminoglycosides / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D003001:Cloning, Molecular; D005798:Genes, Bacterial; D008969:Molecular Sequence Data; D005810:Multigene Family; D048630:Polyketide Synthases / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D013302:Streptomyces / Q000201:enzymology* / Q000235:genetics*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; C545292:tirandamycin C; C545293:tirandamycin D; C003608:tirandamycin A; C021492:tirandamycin B; D048630:Polyketide Synthases