Yuhui Sun, Hui Hong, Markiyan Samborskyy, Tatiana Mironenko, Peter F. Leadlay, and Stephen F. Haydock*
Microbiology 2006, 152(Pt 12):3507-3515
First published: 1 December 2006
Meridamycin is a non-immunosuppressant, FKBP-binding macrocyclic polyketide, which has major potential as a neuroprotectant in a range of neurodegenerative disorders including dementia, Parkinson's disease and ischaemicstroke. A biosynthetic cluster predicted to encode biosynthesis of meridamycin was cloned from the prolific secondary-metabolite-producing strain Streptomyces sp. DSM 4137, not previously known to produce this compound, and specific genedeletion was used to confirm the role of this cluster in the biosynthesis of meridamycin. The meridamycin modular polyketide synthase consists of 14 extension modules distributed between three giant multienzyme proteins. The terminal module is flanked by a highly unusual cytochrome P450-like domain. The characterization of the meridamycin biosynthetic locus in this readily manipulated streptomycete species opens the way to the engineering of new, altered meridamycinsof potential therapeutic importance.
Tiangang Liu, Delin You, Chiara Valenzano, Yuhui Sun, Jialiang Li, Qing Yu, Xiufen Zhou, David E. Cane, and Zixin Deng*
Chemistry & Biology 2006, 13(9):945-955
First published: 22 September 2006
The polyketide synthase (PKS) for the biosynthesis of the polyether nanchangmycin lacks an apparent thioesterase comparable to the type I thioesterase domains of the modular PKSs responsible for macrolide biosynthesis. Three candidate polyether chain-releasing factors were examined. Both the putative CR domain and the NanE protein appeared to be genetically relevant. Among the three heterologously expressed soluble proteins (recombinant CR domain, the ACP-CR didomain, and NanE) tested, only NanE hydrolyzed the polyether-SNAC. By contrast, recombinant DEBS TE from the erythromycin pathway, and the recombinant MonAX, a type II TE associated with the polyether monensin biosynthesis for which a homolog has not been detected in the nanchangmycin cluster, hydrolyzed a diketide-SNAC but not the polyether-SNAC. We could thus conclude that NanE is a dedicated thioesterase mediating the specific release of the polyether chain during nanchangmycin biosynthesis.
Yuhui Sun, and ZixinDeng*
中国抗生素杂志 2006, 31(1):6-14+18
Chinese Journal of Antibiotics 2006, 31(1):6-14+18 (Chinese)
Published online: 25 January 2006
Polyketide compounds and their biosynthesis by combinatorial approaches had received great attention as a cross-disciplinary subject in a new field of chemical biology for its importance and great potential to creat brand new drug in future. In this review, we hope to summarize methods and technologies which had been developed over past ten years or so for the imaginative discovery of novel polyketide compounds by combinatorial biosynthesis, which incorpotare genetic, chemical and biochemical, bioinformatic and biotechnological approaches.