Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, 185 Donghu Road., Wuhan, 430071, China.
State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
Angew Chem Int Ed Engl. 2018 May 14;57(20):5823-5827. doi: 10.1002/anie.201802805. Epub 2018 Apr 14.
Polyketides are a large family of pharmaceutically important natural products, and the structural modification of their scaffolds is significant for drug development. Herein, we report high-resolution X-ray crystal structures of the broadly selective acyltransferase (AT) from the splenocin polyketide synthase (SpnD-AT) in the apo form and in complex with benzylmalonyl and pentynylmalonyl extender unit mimics. These structures revealed the molecular basis for the stereoselectivity and substrate specificity of SpnD-AT, and enabled the engineering of the industrially important Ery-AT6 to broaden its substrate scope to include three new types of extender units.
聚酮类化合物是一类具有重要药用价值的天然产物，其结构修饰对于药物开发具有重要意义。在此，我们报道了广谱选择性酰基转移酶（AT）来自 splenocin 聚酮合酶（SpnD-AT）的高分辨率 X 射线晶体结构，该酶呈apo 形式和与苄基丙二酰和戊烯基丙二酰延伸单元类似物结合的形式。这些结构揭示了 SpnD-AT 立体选择性和底物特异性的分子基础，并使工业上重要的 Ery-AT6 得以工程化，从而扩大其底物范围，包括三种新型延伸单元。
