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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 27 14-24 (2020)
Related entries: 6sek, 6sem, 6sf0

Cited: 19 times
EuropePMC logo PMID: 31873300

Abstract

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-Å 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.

Articles - 6se3 mentioned but not cited (2)

  1. Ancestral reconstruction of mammalian FMO1 enables structural determination, revealing unique features that explain its catalytic properties. Bailleul G, Nicoll CR, Mascotti ML, Mattevi A, Fraaije MW. J Biol Chem 296 100221 (2021)
  2. Investigating the biochemical signatures and physiological roles of the FMO family using molecular phylogeny. Nicoll CR, Mascotti ML. BBA Adv 4 100108 (2023)


Reviews citing this publication (2)

  1. Ancestral sequence reconstruction as a tool to study the evolution of wood decaying fungi. Ayuso-Fernández I, Molpeceres G, Camarero S, Ruiz-Dueñas FJ, Martínez AT. Front Fungal Biol 3 1003489 (2022)
  2. Multiple Functions of Compatible Solute Ectoine and Strategies for Constructing Overproducers for Biobased Production. Zhang W, Liu K, Kong F, Ye T, Wang T. Mol Biotechnol (2023)

Articles citing this publication (15)

  1. Engineering of Ancestors as a Tool to Elucidate Structure, Mechanism, and Specificity of Extant Terpene Cyclase. Schriever K, Saenz-Mendez P, Rudraraju RS, Hendrikse NM, Hudson EP, Biundo A, Schnell R, Syrén PO. J Am Chem Soc 143 3794-3807 (2021)
  2. Flavin-Containing Monooxygenases Are Conserved Regulators of Stress Resistance and Metabolism. Huang S, Howington MB, Dobry CJ, Evans CR, Leiser SF. Front Cell Dev Biol 9 630188 (2021)
  3. Resurrecting Enzymes by Ancestral Sequence Reconstruction. Mascotti ML. Methods Mol Biol 2397 111-136 (2022)
  4. The Single-Component Flavin Reductase/Flavin-Dependent Halogenase AetF is a Versatile Catalyst for Selective Bromination and Iodination of Arenes and Olefins. Jiang Y, Snodgrass HM, Zubi YS, Roof CV, Guan Y, Mondal D, Honeycutt NH, Lee JW, Lewis RD, Martinez CA, Lewis JC. Angew Chem Int Ed Engl 61 e202214610 (2022)
  5. Deciphering the evolution of flavin-dependent monooxygenase stereoselectivity using ancestral sequence reconstruction. Chiang CH, Wymore T, Rodríguez Benítez A, Hussain A, Smith JL, Brooks CL, Narayan ARH. Proc Natl Acad Sci U S A 120 e2218248120 (2023)
  6. Evolution of enzyme functionality in the flavin-containing monooxygenases. Bailleul G, Yang G, Nicoll CR, Mattevi A, Fraaije MW, Mascotti ML. Nat Commun 14 1042 (2023)
  7. Substrate binding tunes the reactivity of hispidin 3-hydroxylase, a flavoprotein monooxygenase involved in fungal bioluminescence. Tong Y, Trajkovic M, Savino S, van Berkel WJH, Fraaije MW. J Biol Chem 295 16013-16022 (2020)
  8. Topiary: Pruning the manual labor from ancestral sequence reconstruction. Orlandi KN, Phillips SR, Sailer ZR, Harman JL, Harms MJ. Protein Sci 32 e4551 (2023)
  9. Ancestral lysosomal enzymes with increased activity harbor therapeutic potential for treatment of Hunter syndrome. Hendrikse NM, Sandegren A, Andersson T, Blomqvist J, Makower Å, Possner D, Su C, Thalén N, Tjernberg A, Westermark U, Rockberg J, Svensson Gelius S, Syrén PO, Nordling E. iScience 24 102154 (2021)
  10. Reaction Mechanism of Ancestral l-Lys α-Oxidase from Caulobacter Species Studied by Biochemical, Structural, and Computational Analysis. Motoyama T, Yamamoto Y, Ishida C, Hasebe F, Kawamura Y, Shigeta Y, Ito S, Nakano S. ACS Omega 7 44407-44419 (2022)
  11. Treatment of wild-type mice with 2,3-butanediol, a urinary biomarker of Fmo5 -/- mice, decreases plasma cholesterol and epididymal fat deposition. Veeravalli S, Varshavi D, Scott FH, Varshavi D, Pullen FS, Veselkov K, Phillips IR, Everett JR, Shephard EA. Front Physiol 13 859681 (2022)
  12. A Cold-Active Flavin-Dependent Monooxygenase from Janthinobacterium svalbardensis Unlocks Applications of Baeyer-Villiger Monooxygenases at Low Temperature. Chánique AM, Polidori N, Sovic L, Kracher D, Assil-Companioni L, Galuska P, Parra LP, Gruber K, Kourist R. ACS Catal 13 3549-3562 (2023)
  13. Genomic Survey of Flavin Monooxygenases in Wild and Cultivated Rice Provides Insight into Evolution and Functional Diversities. Gaba Y, Bhowal B, Pareek A, Singla-Pareek SL. Int J Mol Sci 24 4190 (2023)
  14. Guiding discovery of protein sequence-structure-function modeling. Hussain A, Brooks Iii CL. Bioinformatics 40 btae002 (2024)
  15. Structural basis of regioselective tryptophan dibromination by the single-component flavin-dependent halogenase AetF. Gäfe S, Niemann HH. Acta Crystallogr D Struct Biol 79 596-609 (2023)


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