Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
J R Soc Interface. 2013 May 29;10(85):20130297. doi: 10.1098/rsif.2013.0297. Print 2013 Aug 6.
Polyketide natural products act as a broad range of therapeutics, including antibiotics, immunosuppressants and anti-cancer agents. This therapeutic diversity stems from the structural diversity of these small molecules, many of which are produced in an assembly line manner by modular polyketide synthases. The acyltransferase (AT) domains of these megasynthases are responsible for selection and incorporation of simple monomeric building blocks, and are thus responsible for a large amount of the resulting polyketide structural diversity. The substrate specificity of these domains is often targeted for engineering in the generation of novel, therapeutically active natural products. This review outlines recent developments that can be used in the successful engineering of these domains, including AT sequence and structural data, mechanistic insights and the production of a diverse pool of extender units. It also provides an overview of previous AT domain engineering attempts, and concludes with proposed engineering approaches that take advantage of current knowledge. These approaches may lead to successful production of biologically active 'unnatural' natural products.
聚酮类天然产物作为广泛的治疗药物，包括抗生素、免疫抑制剂和抗癌剂。这种治疗多样性源于这些小分子的结构多样性，其中许多小分子是由模块化聚酮合酶以装配线的方式产生的。这些巨型合酶的酰基转移酶 (AT) 结构域负责选择和整合简单的单体构建块，因此负责产生大量的聚酮结构多样性。这些结构域的底物特异性通常是针对新型治疗性天然产物的工程设计而靶向的。本综述概述了可用于成功工程这些结构域的最新进展，包括 AT 序列和结构数据、机制见解以及扩展单元的多样化库的生产。它还概述了以前的 AT 结构域工程尝试，并以利用当前知识的建议工程方法结束。这些方法可能会导致具有生物活性的“非天然”天然产物的成功生产。
