Smith Janet L, Skiniotis Georgios, Sherman David H
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Curr Opin Struct Biol. 2015 Apr;31:9-19. doi: 10.1016/j.sbi.2015.02.014. Epub 2015 Mar 16.
Modular polyketide synthases (PKS) produce a vast array of bioactive molecules that are the basis of many highly valued pharmaceuticals. The biosynthesis of these compounds is based on ordered assembly lines of multi-domain modules, each extending and modifying a specific chain-elongation intermediate before transfer to the next module for further processing. The first 3D structures of a full polyketide synthase module in different functional states were obtained recently by electron cryo-microscopy. The unexpected module architecture revealed a striking evolutionary divergence of the polyketide synthase compared to its metazoan fatty acid synthase homolog, as well as remarkable conformational rearrangements dependent on its biochemical state during the full catalytic cycle. The design and dynamics of the module are highly optimized for both catalysis and fidelity in the construction of complex, biologically active natural products.
模块化聚酮合酶（PKS）可产生大量生物活性分子，这些分子是许多高价值药物的基础。这些化合物的生物合成基于多结构域模块的有序装配线，每个模块在将特定的链延伸中间体转移到下一个模块进行进一步加工之前，都会对其进行延伸和修饰。最近，通过电子冷冻显微镜获得了处于不同功能状态的完整聚酮合酶模块的首批三维结构。意外的模块结构揭示了聚酮合酶与其后生动物脂肪酸合酶同源物相比存在显著的进化差异，以及在整个催化循环中依赖于其生化状态的显著构象重排。该模块的设计和动力学在催化和构建复杂的生物活性天然产物时的保真度方面都进行了高度优化。
