Benjamin Nji Wandi, Pedro Dinis, Vilja Siitonen, Gunter Schneider, Robert Schnell, Mikko Metsä-Ketelä
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引用次数: 0
Abstract
Anthracyclines are microbial natural products with important antiproliferative bioactivities that are widely used in anticancer chemotherapy. Several anthracyclines, including nogalamycin and kosinostatin, contain a 1-hydroxyl group, which is installed by an atypical two-component mono-oxygenase system. Here, we clarify the structural and mechanistic basis for 1-hydroxylation. We present the crystal structure of the NADPH-dependent reductase SwaQ2 in complex with doxorubicin, which indicates that the reaction is initiated by quinone reduction. The reduced anthracycline ligand may react with molecular oxygen, leading to the formation of a peroxide intermediate similar to flavin chemistry. The structures of the polyketide cyclase-like SnoaL2, involved in nogalamycin biosynthesis, in complex with substrate and product reveal a novel catalytic tetrad, which is used to stabilize a reduced reaction intermediate to direct the reaction toward 1-hydroxylation. Furthermore, we report the characterization of several unknown anthracycline 1-hydroxylases, which display varied substrate profiles. The structure of polyketide cyclase-like KstA15 from the kosinostatin pathway enabled structure-based protein engineering to expand the substrate specificity of the enzyme to include glycosylated anthracyclines. Our work provides insight into how reductase-hydroxylase two-component systems circumvent the need for organic cofactors or metal ions to catalyze monooxygenations in several anthracycline pathways.
期刊介绍:
ACS Catalysis is an esteemed journal that publishes original research in the fields of heterogeneous catalysis, molecular catalysis, and biocatalysis. It offers broad coverage across diverse areas such as life sciences, organometallics and synthesis, photochemistry and electrochemistry, drug discovery and synthesis, materials science, environmental protection, polymer discovery and synthesis, and energy and fuels.
The scope of the journal is to showcase innovative work in various aspects of catalysis. This includes new reactions and novel synthetic approaches utilizing known catalysts, the discovery or modification of new catalysts, elucidation of catalytic mechanisms through cutting-edge investigations, practical enhancements of existing processes, as well as conceptual advances in the field. Contributions to ACS Catalysis can encompass both experimental and theoretical research focused on catalytic molecules, macromolecules, and materials that exhibit catalytic turnover.