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.

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.

聚酮化合物的组合生物合成是当前国际化学与生物学交叉学科研究的热点之一，也正在发展成为药物创新超常规的重要手段。本文对近十年来聚酮化合物，特别是I型聚酮化合物的组合生物合成的常用技术和方法学发展进行了回顾和展望。

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.