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Deciphering Pactamycin Biosynthesis and Engineered Production of New Pactamycin Analogues
Author(s) -
Ito Takuya,
Roongsawang Niran,
Shirasaka Norifumi,
Lu Wanli,
Flatt Patricia M.,
Kasanah Noer,
Miranda Cristobal,
Mahmud Taifo
Publication year - 2009
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200900339
Subject(s) - biosynthesis , gene cluster , biochemistry , biology , gene , polyketide , streptomyces , chemistry , genetics , bacteria
Pactamycin is an aminocyclopentitol‐derived natural product that has potent antibacterial and antitumor activities. Sequence analysis of an 86 kb continuous region of the chromosome from Streptomyces pactum ATCC 27456 revealed a gene cluster involved in the biosynthesis of pactamycin. Gene inactivation of the Fe‐S radical SAM oxidoreductase ( ptmC ) and the glycosyltransferase ( ptmJ ), individually abrogated pactamycin biosynthesis; this confirmed the involvement of the ptm gene cluster in pactamycin biosynthesis. The polyketide synthase gene ( ptmQ ) was found to support 6‐methylsalicylic acid (6‐MSA) synthesis in a heterologous host, S. lividans T7. In vivo inactivation of ptmQ in S. pactum impaired pactamycin and pactamycate production but led to production of two new pactamycin analogues, de‐6‐MSA‐pactamycin and de‐6‐MSA‐pactamycate. The new compounds showed equivalent cytotoxic and antibacterial activities with the corresponding parent molecules and shed more light on the structure–activity relationship of pactamycin.