A new post-PKS modification process in the carbamoyltransferase gene inactivation strain of Streptomyces hygroscopicus 17997.
Genetic manipulation of geldanamycin (GDM) producer Streptomyces species is a rational approach to understand biosynthesis processes and create new analogues. In this study, the carbamoyltransferase gene gdmN was inactivated by insertion of an apramycin-resistance gene aac3 (IV) into the genome of the geldanamycin-producing strain Streptomyces hygroscopicus 17997. GDM analogues produced by this mutant strain were isolated and characterized, such as new compound 4,5-dihydro-7-O-descarbamoyl-7-hydroxy-19-O-glycylgeldanamycin. This compound could be converted to compound 4,5-dihydro-19-O-glycylgeldanamycin, another new GDM analogue, by a strain of Streptomyces hygroscopicus 17997 in which the GDM-pks was inactivated. These new compounds exhibited reductions of cytotoxicity against HepG2 cancer cells, but increases of aqueous solubility. These results suggest that a new post-polyketide synthase modification was involved in this process to produce new GDM analogues.
Li
Yonghai
Y
Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
He
Weiqing
W
Wang
Yucheng
Y
Wang
Yiguang
Y
Shao
Rongguang
R
D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019878:Carboxyl and Carbamoyl Transferases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D020868:Gene Silencing; D005818:Genetic Engineering; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005810:Multigene Family; D016254:Mutagenesis, Insertional; D009328:Nebramycin / Q000031:analogs & derivatives / Q000494:pharmacology; D048630:Polyketide Synthases / Q000378:metabolism; D013302:Streptomyces / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*
C532986:4,5-dihydro-19-O-glycylgeldanamycin; C532985:4,5-dihydro-7-O-descarbamoyl-7-hydroxy-19-O-glycylgeldanamycin; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D003603:Cytotoxins; D047029:Lactams, Macrocyclic; D009328:Nebramycin; C011666:apramycin; D048630:Polyketide Synthases; D019878:Carboxyl and Carbamoyl Transferases; C001277:geldanamycin