Identification and Characterization of the Biosynthetic Gene Cluster of Thiolutin, a Tumor Angiogenesis Inhibitor, in Saccharothrix algeriensis NRRL B-24137

Author(s):

Sheng Huang, Ming Him Tong, Zhiwei Qin, Zixin Deng, Hai Deng and Yi Yu   Pages 277 - 284 ( 8 )

Abstract:

In this study, a new dithiolopyrrolone biosynthetic pathway was identified in Saccharothrix algeriensis NRRL B-24137, which was reported to produce a variety of dithiolopyrrolone natural products including thiolutin, a potential drug candidate for tumor angiogenesis inhibition. Bioinformatics analysis of the cluster revealed that it contains all the essential genes for holothin core biosynthesis and several other auxiliary genes. Interestingly, heterologous expression of the gene cluster in Streptomyces albus only induced the production of holomycin, implying that the gene responsible for the N₄-methylation and the gene(s) involved in the formation of various acylated chains on N₇ position of the holothin may locate outside the gene cluster. Incubation of holomycin with S-adenosyl-L-methionine (SAM) in the cell-free extract of Sa. algeriensis resulted in the production of thiolutin, suggesting that the N₄-methyl group of thiolutin is originated from SAM, and the N₄-methylation could be in the late stage of biosynthesis of thiolutin type dithiolopyrrolones. An evolution-based model for biosynthesis of thiolutin and its analogs was further proposed based on these results.

Keywords:

Saccharothrix algeriensis, thiolutin, dithiolopyrrolone, biosynthesis, heterologous expression.

Affiliation:

, , , , , Key Laboratory of Combinatory Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, 185 East Lake Road, Wuhan 430071 P. R. China.

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