Cloning and sequencing of the kedarcidin biosynthetic gene cluster from Streptoalloteichus sp. ATCC 53650 revealing new insights into biosynthesis of the enediyne family of antitumor antibiotics.
Enediyne natural product biosynthesis is characterized by a convergence of multiple pathways, generating unique peripheral moieties that are appended onto the distinctive enediyne core. Kedarcidin (KED) possesses two unique peripheral moieties, a (R)-2-aza-3-chloro-β-tyrosine and an iso-propoxy-bearing 2-naphthonate moiety, as well as two deoxysugars. The appendage pattern of these peripheral moieties to the enediyne core in KED differs from the other enediynes studied to date with respect to stereochemical configuration. To investigate the biosynthesis of these moieties and expand our understanding of enediyne core formation, the biosynthetic gene cluster for KED was cloned from Streptoalloteichus sp. ATCC 53650 and sequenced. Bioinformatics analysis of the ked cluster revealed the presence of the conserved genes encoding for enediyne core biosynthesis, type I and type II polyketide synthase loci likely responsible for 2-aza-l-tyrosine and 3,6,8-trihydroxy-2-naphthonate formation, and enzymes known for deoxysugar biosynthesis. Genes homologous to those responsible for the biosynthesis, activation, and coupling of the l-tyrosine-derived moieties from C-1027 and maduropeptin and of the naphthonate moiety from neocarzinostatin are present in the ked cluster, supporting 2-aza-l-tyrosine and 3,6,8-trihydroxy-2-naphthoic acid as precursors, respectively, for the (R)-2-aza-3-chloro-β-tyrosine and the 2-naphthonate moieties in KED biosynthesis.
Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Jeremy R
JR
Lohman
Sheng-Xiong
SX
Huang
Geoffrey P
GP
Horsman
Paul E
PE
Dilfer
Tingting
T
Huang
Yihua
Y
Chen
Evelyn
E
Wendt-Pienkowski
Ben
B
Shen
D000192:Actinomycetales / Q000201:enzymology / Q000235:genetics*; D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D053898:Biosynthetic Pathways / Q000235:genetics*; D003001:Cloning, Molecular; D003516:Cycloparaffins / Q000378:metabolism*; D053281:Enediynes / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000096:biosynthesis / Q000235:genetics; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics; D005798:Genes, Bacterial; D036341:Intercellular Signaling Peptides and Proteins; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D005810:Multigene Family; D009281:Naphthalenes / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D017422:Sequence Analysis, DNA
D000903:Antibiotics, Antineoplastic; D001426:Bacterial Proteins; D003516:Cycloparaffins; D053281:Enediynes; D036341:Intercellular Signaling Peptides and Proteins; D009281:Naphthalenes; D010455:Peptides; C069636:kedarcidin peptide; C080542:kedarcidin chromophore; D064429:Fatty Acid Synthases; D004851:Epoxide Hydrolases