6u9i

Publication Abstract from PubMed

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 assembly of diastereomerically distinct and enantiomerically antipodal metabolites, have remained largely uncharacterized. Brevianamide A represents a basic form of the sub-family bearing a dioxopiperazine core and a rare 3-spiro-psi-indoxyl skeleton. Here, we 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/semi-pinacolase that specifies selective production of the natural product. Structural elucidation, molecular modeling, and mutational analysis of BvnE, and quantum chemical calculations provided mechanistic insights into the diastereoselective formation of the 3-spiro-psi-indoxyl moiety in Brevianamide A. This occurs through a BvnE-controlled semi-pinacol rearrangement and a subsequent spontaneous intramolecular [4+2] hetero-Diels-Alder cycloaddition.

Fungal-derived brevianamide assembly by a stereoselective semipinacolase.,Ye Y, Du L, Zhang X, Newmister SA, McCauley M, Alegre-Requena JV, Zhang W, Mu S, Minami A, Fraley AE, Adrover-Castellano ML, Carney NA, Shende VV, Qi F, Oikawa H, Kato H, Tsukamoto S, Paton RS, Williams RM, Sherman DH, Li S Nat Catal. 2020 Jun;3(6):497-506. doi: 10.1038/s41929-020-0454-9. Epub 2020 May, 18. PMID:32923978^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.