Maier Timm, Leibundgut Marc, Ban Nenad
Institute of Molecular Biology and Biophysics, ETH Zurich, 8092 Zurich, Switzerland.
Science. 2008 Sep 5;321(5894):1315-22. doi: 10.1126/science.1161269.
Mammalian fatty acid synthase is a large multienzyme that catalyzes all steps of fatty acid synthesis. We have determined its crystal structure at 3.2 angstrom resolution covering five catalytic domains, whereas the flexibly tethered terminal acyl carrier protein and thioesterase domains remain unresolved. The structure reveals a complex architecture of alternating linkers and enzymatic domains. Substrate shuttling is facilitated by flexible tethering of the acyl carrier protein domain and by the limited contact between the condensing and modifying portions of the multienzyme, which are mainly connected by linkers rather than direct interaction. The structure identifies two additional nonenzymatic domains: (i) a pseudo-ketoreductase and (ii) a peripheral pseudo-methyltransferase that is probably a remnant of an ancestral methyltransferase domain maintained in some related polyketide synthases. The structural comparison of mammalian fatty acid synthase with modular polyketide synthases shows how their segmental construction allows the variation of domain composition to achieve diverse product synthesis.
哺乳动物脂肪酸合酶是一种大型多酶复合体，催化脂肪酸合成的所有步骤。我们已确定其在3.2埃分辨率下的晶体结构，涵盖五个催化结构域，而柔性连接的末端酰基载体蛋白和硫酯酶结构域仍未解析。该结构揭示了由交替连接子和酶结构域组成的复杂架构。酰基载体蛋白结构域的柔性连接以及多酶复合体缩合和修饰部分之间有限的接触促进了底物穿梭，这两部分主要通过连接子相连，而非直接相互作用。该结构还鉴定出另外两个非酶结构域：（i）一个假酮还原酶和（ii）一个外周假甲基转移酶，后者可能是在一些相关聚酮合酶中保留的祖先甲基转移酶结构域的残余部分。哺乳动物脂肪酸合酶与模块化聚酮合酶的结构比较表明，它们的分段构建如何允许结构域组成发生变化以实现多样的产物合成。
