Journal
NATURE CHEMISTRY
Volume 12, Issue 7, Pages 620-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41557-020-0467-7
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Funding
- National Natural Science Foundation of China [21625201, 21661140001, 21961142010, 91853202, 21521003]
- National Key Research and Development Program of China [2017YFA0505200]
- Beijing Outstanding Young Scientist Program [BJJWZYJH01201910001001]
- CAMS Innovation Fund for Medical Sciences [CIFMS-2016-I2M-3-012, 2019-I2M-1-005]
- Drug Innovation Major Project [2018ZX09711001-001-006]
- Key Project at Central Government Level for the Ability Establishment of Sustainable Use for Valuable Chinese Medicine Resources [2060302]
- JSPS A3 Foresight Program
- Fundamental Research Funds for the Central Universities [2017PT35001]
- Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) [U1501501]
- National Science Foundation [CHE-1764328, OCI-1053575]
- Postdoctoral Fellowship of Peking-Tsinghua Center for Life Sciences
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The Diels-Alder reaction is one of the most powerful and widely used methods in synthetic chemistry for the stereospecific construction of carbon-carbon bonds. Despite the importance of Diels-Alder reactions in the biosynthesis of numerous secondary metabolites, no naturally occurring stand-alone Diels-Alderase has been demonstrated to catalyse intermolecular Diels-Alder transformations. Here we report a flavin adenine dinucleotide-dependent enzyme, Morusalba Diels-Alderase (MaDA), from Morus cell cultures, that catalyses an intermolecular [4+2] cycloaddition to produce the natural isoprenylated flavonoid chalcomoracin with a high efficiency and enantioselectivity. Density functional theory calculations and preliminary measurements of the kinetic isotope effects establish a concerted but asynchronous pericyclic pathway. Structure-guided mutagenesis and docking studies demonstrate the interactions of MaDA with the diene and dienophile to catalyse the [4+2] cycloaddition. MaDA exhibits a substrate promiscuity towards both dienes and dienophiles, which enables the expedient syntheses of structurally diverse natural products. We also report a biosynthetic intermediate probe (BIP)-based target identification strategy used to discover MaDA.
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