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Publication Abstract from PubMed

Diels-Alder (DA) [4 + 2]-cycloaddition reactions rank among the most powerful transformations in synthetic organic chemistry; biosynthetic examples, however, are few and far between. We report here a heme-binding cyclase, AbmU, that catalyzes an essential [4 + 2] cycloaddition during neoabyssomicin scaffold assembly. In vivo genetic and in vitro biochemical analyses strongly suggest that AbmU catalyzes an intramolecular and stereoselective [4 + 2] cycloaddition to form a spirotetronate skeleton from an acyclic substrate featuring both a terminal 1,3-diene and an exo-methylene group. Biochemical assays and X-ray diffraction analyses reveal that AbmU binds nonspecifically to a heme b cofactor and that this association does not play a catalytic role in AbmU catalysis. A detailed study of the AbmU crystal structure reveals a unique mode of substrate binding and reaction catalysis; His160 forms a H-bond with the C-1 carbonyl O-atom of the acyclic substrate, and the imidazole of the same amino acid directs the tetronate moiety of acyclic substrate toward the terminal Delta(10,11), Delta(12,13)-diene moiety, thereby facilitating intramolecular DA chemistry. Our findings expand upon what is known about mechanistic diversities available to biosynthetic [4 + 2] cyclases and help to lay the foundation for the use of AbmU in possible industrial applications.

Nonspecific Heme-Binding Cyclase, AbmU, Catalyzes [4 + 2] Cycloaddition during Neoabyssomicin Biosynthesis.,Li Q, Ding W, Tu J, Chi C, Huang H, Ji X, Yao Z, Ma M, Ju J ACS Omega. 2020 Aug 6;5(32):20548-20557. doi: 10.1021/acsomega.0c02776., eCollection 2020 Aug 18. PMID:32832808^[1]

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