Deciphering pactamycin biosynthesis and engineered production of new pactamycin analogues.
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.
Ito
Takuya
T
Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331-3507, USA.
Roongsawang
Niran
N
Shirasaka
Norifumi
N
Lu
Wanli
W
Flatt
Patricia M
PM
Kasanah
Noer
N
Miranda
Cristobal
C
Mahmud
Taifo
T
D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D045744:Cell Line, Tumor; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D010142:Pactamycin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D010142:Pactamycin; D048630:Polyketide Synthases