Faculty of Biology, University of Freiburg, Schänzlestrasse 1, 79104, Freiburg, Germany.
Institute of Pharmaceutical Sciences, University of Freiburg, Albertstr. 25, 79104, Freiburg, Germany.
Angew Chem Int Ed Engl. 2021 Dec 20;60(52):26960-26970. doi: 10.1002/anie.202109384. Epub 2021 Nov 10.
The medically important bacterial aromatic polyketide natural products typically feature a planar, polycyclic core structure. An exception is found for the rubromycins, whose backbones are disrupted by a bisbenzannulated [5,6]-spiroketal pharmacophore that was recently shown to be assembled by flavin-dependent enzymes. In particular, a flavoprotein monooxygenase proved critical for the drastic oxidative rearrangement of a pentangular precursor and the installment of an intermediate [6,6]-spiroketal moiety. Here we provide structural and mechanistic insights into the control of catalysis by this spiroketal synthase, which fulfills several important functions as reductase, monooxygenase, and presumably oxidase. The enzyme hereby tightly controls the redox state of the substrate to counteract shunt product formation, while also steering the cleavage of three carbon-carbon bonds. Our work illustrates an exceptional strategy for the biosynthesis of stable chroman spiroketals.
医学上重要的细菌芳香聚酮天然产物通常具有平面、多环核心结构。但rubromycins 是一个例外，其骨架被一个双苯并[5,6]-螺缩酮药效团所破坏，该药效团最近被证明是由黄素依赖的酶组装而成。特别是，黄素蛋白单加氧酶被证明对五角形前体的剧烈氧化重排以及中间[6,6]-螺缩酮部分的安装至关重要。在这里，我们提供了对这种螺缩酮合酶催化控制的结构和机制见解，该酶作为还原酶、单加氧酶和可能的氧化酶具有多种重要功能。该酶通过严格控制底物的氧化还原状态来抵抗分流产物的形成，同时还控制着三个碳-碳键的断裂。我们的工作说明了一种用于稳定色满螺缩酮生物合成的特殊策略。
