Cloning, Sequencing, Analysis, and Heterologous Expression of the Fredericamycin Biosynthetic Gene Cluster from Streptomyces griseus
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- 作者：Evelyn Wendt-Pienkowski ; Yong Huang ; Jian Zhang ; Bensheng Li ; Hao Jiang ; Hyungjin Kwon ; C. Richard Hutchinson ; and Ben Shen
- 刊名：Journal of the American Chemical Society
- 出版年：2005
- 出版时间：November 30, 2005
- 年：2005
- 卷：127
- 期：47
- 页码：16442 - 16452
- 全文大小：462K
- 年卷期：v.127,no.47(November 30, 2005)
- ISSN：1520-5126
文摘
Fredericamycin (FDM) A, a pentadecaketide featuring two sets of peri-hydroxy tricyclic aromaticmoieties connected through a unique chiral spiro carbon center, exhibits potent cytotoxicity and has beenstudied as a new type of anticancer drug lead because of its novel molecular architecture. The fdm genecluster was localized to 33-kb DNA segment of Streptomyces griseus ATCC 49344, and its involvement inFDM A biosynthesis was proven by gene inactivation, complementation, and heterologous expressionexperiments. The fdm cluster consists of 28 open reading frames (ORFs), encoding a type II polyketidesynthase (PKS) and tailoring enzymes as well as several regulatory and resistance proteins. The FDMPKS features a KS
subunit with heretofore unseen tandem cysteines at its active site, a KS
subunit thatis distinct phylogenetically from KS of hexa-, octa-, or decaketide PKSs, and a dedicated phosphopantetheinyl transferase. Further study of the FDM PKS could provide new insight into how a type II PKScontrols chain length in aromatic polyketide biosynthesis. The availability of the fdm genes, in vivocharacterization of the fdm cluster in S. griseus, and heterologous expression of the fdm cluster inStreptomyces albus set the stage to investigate FDM A biosynthesis and engineer the FDM biosyntheticmachinery for the production of novel FDM A analogues.
subunit with heretofore unseen tandem cysteines at its active site, a KS subunit thatis distinct phylogenetically from KS of hexa-, octa-, or decaketide PKSs, and a dedicated phosphopantetheinyl transferase. Further study of the FDM PKS could provide new insight into how a type II PKScontrols chain length in aromatic polyketide biosynthesis. The availability of the fdm genes, in vivocharacterization of the fdm cluster in S. griseus, and heterologous expression of the fdm cluster inStreptomyces albus set the stage to investigate FDM A biosynthesis and engineer the FDM biosyntheticmachinery for the production of novel FDM A analogues.