Journal
NATURE CATALYSIS
Volume 3, Issue 6, Pages 497-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41929-020-0454-9
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Funding
- National Key Research and Development Program [2019YFA0905100, 2019YFA0706900]
- National Natural Science Foundation of China [21472204, 31872729, 31800041]
- National Institutes of Health [R35 GM118101]
- Hans W. Vahlteich Professorship [R01 CA070375]
- Shandong Provincial Natural Science Foundation [ZR2019ZD20, ZR201807060986]
- National Postdoctoral Innovative Talents Support Program [BX20180325]
- China Postdoctoral Science Foundation [2019M652500]
- NSF [CHE-0840456]
- National Institute of General Medical Sciences [AGM-12006]
- National Cancer Institute [ACB-12002]
- National Science Foundation [ACI-1548562, ACI-1532235, ACI-1532236]
- University of Colorado Boulder and Colorado State University
- Extreme Science and Engineering Discovery Environment (XSEDE) [TG-CHE180056]
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The biogenesis and stereochemical origin of many natural products remain unknown. Now the biosynthetic pathway of brevianamide A is elucidated. An isomerase is discovered that can catalyse pinacol rearrangement without a cofactor and determine the stereochemistry of the bicyclo[2.2.2]diazaoctane ring. Fungal bicyclo[2.2.2]diazaoctane indole alkaloids represent an important family of natural products with a wide spectrum of biological activities. Although biomimetic total syntheses of representative compounds have been reported, the details of their biogenesis, especially the mechanisms for the assembly of diastereomerically distinct and enantiomerically antipodal metabolites, have remained largely uncharacterized. Brevianamide A represents a basic form of the subfamily bearing a dioxopiperazine core and a rare 3-spiro-psi-indoxyl skeleton. In this study, we have identified the brevianamide A biosynthetic gene cluster from Penicillium brevicompactum NRRL 864 and elucidated the metabolic pathway. BvnE was revealed to be an essential isomerase/semipinacolase that specifies the selective production of the natural product. Structural elucidation, molecular modelling and mutational analysis of BvnE as well as quantum chemical calculations have provided mechanistic insights into the diastereoselective formation of the 3-spiro-psi-indoxyl moiety in brevianamide A. This occurs through a BvnE-controlled semipinacol rearrangement and a subsequent spontaneous intramolecular [4+2] hetero-Diels-Alder cycloaddition.
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