Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea.
J Antibiot (Tokyo). 2010 Aug;63(8):434-41. doi: 10.1038/ja.2010.71. Epub 2010 Jun 30.
Rapamycin and its analogs are clinically important macrolide compounds produced by Streptomyces hygroscopicus. They exhibit antifungal, immunosuppressive, antitumor, neuroprotective and antiaging activities. The core macrolactone ring of rapamycin is biosynthesized by hybrid type I modular polyketide synthase (PKS)/nonribosomal peptide synthetase systems primed with 4,5-dihydrocyclohex-1-ene-carboxylic acid. The linear polyketide chain is condensed with pipecolate by peptide synthetase, followed by cyclization to form the macrolide ring and modified by a series of post-PKS tailoring steps. The aim of this review was to outline past and recent advances in the biosynthesis and regulation of rapamycin, with an emphasis on the distinguished contributions of Professor Demain to the study of rapamycin. In addition, this article describes the biological activities as well as mechanism of action of rapamycin and its derivatives. Recent attempts to improve the productivity of rapamycin and generate diverse rapamycin analogs through mutasynthesis and mutagenesis are also introduced, along with some future perspectives.
雷帕霉素及其类似物是由吸水链霉菌产生的具有临床重要意义的大环内酯类化合物。它们具有抗真菌、免疫抑制、抗肿瘤、神经保护和抗衰老活性。雷帕霉素的核心大环内酯环由混合 I 型模块聚酮合酶（PKS）/非核糖体肽合酶系统生物合成，由 4,5-二氢环己-1-烯羧酸引发。线性聚酮链由肽合酶与哌可酸缩合，然后环化形成大环内酯环，并通过一系列 PKS 后修饰步骤进行修饰。本综述的目的是概述雷帕霉素生物合成和调控的过去和最新进展，重点介绍德明教授在雷帕霉素研究方面的杰出贡献。此外，本文还描述了雷帕霉素及其衍生物的生物学活性和作用机制。还介绍了通过突变合成和诱变来提高雷帕霉素产量和产生多种雷帕霉素类似物的最新尝试，以及一些未来展望。
