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Publication Abstract from PubMed

Flavin-containing monooxygenases (FMOs) are ubiquitous in all domains of life and metabolize a myriad of xenobiotics, including toxins, pesticides and drugs. However, despite their pharmacological importance, structural information remains bereft. To further our understanding behind their biochemistry and diversity, we used ancestral-sequence reconstruction, kinetic and crystallographic techniques to scrutinize three ancient mammalian FMOs: AncFMO2, AncFMO3-6 and AncFMO5. Remarkably, all AncFMOs could be crystallized and were structurally resolved between 2.7- and 3.2-A resolution. These crystal structures depict the unprecedented topology of mammalian FMOs. Each employs extensive membrane-binding features and intricate substrate-profiling tunnel networks through a conspicuous membrane-adhering insertion. Furthermore, a glutamate-histidine switch is speculated to induce the distinctive Baeyer-Villiger oxidation activity of FMO5. The AncFMOs exhibited catalysis akin to human FMOs and, with sequence identities between 82% and 92%, represent excellent models. Our study demonstrates the power of ancestral-sequence reconstruction as a strategy for the crystallization of proteins.

Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs.,Nicoll CR, Bailleul G, Fiorentini F, Mascotti ML, Fraaije MW, Mattevi A Nat Struct Mol Biol. 2019 Dec 23. pii: 10.1038/s41594-019-0347-2. doi:, 10.1038/s41594-019-0347-2. PMID:31873300^[1]

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