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1. Flavin oxidation in flavin-dependent N -monooxygenases: Flavin Oxidation in NMO

   https://doi.org/10.1002/pro.3487  

   Robinson, Reeder M. ; Klancher, Catherine A. ; Rodriguez, Pedro J. ; Sobrado, Pablo ( September 2018 , Protein Science)
2. Trapping conformational states of a flavin-dependent N-monooxygenase in crystallo reveals protein and flavin dynamics

   https://doi.org/10.1074/jbc.RA120.014750  

   Campbell, Ashley C. ; Stiers, Kyle M. ; Martin Del Campo, Julia S. ; Mehra-Chaudhary, Ritcha ; Sobrado, Pablo ; Tanner, John J. ( September 2020 , Journal of Biological Chemistry)

   null (Ed.)
3. Spectroscopic evidence for direct flavin-flavin contact in a bifurcating electron transfer flavoprotein

   https://doi.org/10.1074/jbc.RA120.013174  

   Duan, H. Diessel ; Mohamed-Raseek, Nishya ; Miller, Anne-Frances ( September 2020 , Journal of Biological Chemistry)

   null (Ed.)
4. The dynamics of the flavin, NADPH , and active site loops determine the mechanism of activation of class B flavin‐dependent monooxygenases

   https://doi.org/10.1002/pro.4935  

   Pierdominici‐Sottile, Gustavo ; Palma, Juliana ; Ferrelli, María Leticia ; Sobrado, Pablo ( March 2024 , Protein Science)

   Flavin‐dependent monooxygenases (FMOs) constitute a diverse enzyme family that catalyzes crucial hydroxylation, epoxidation, and Baeyer–Villiger reactions across various metabolic pathways in all domains of life. Due to the intricate nature of this enzyme family's mechanisms, some aspects of their functioning remain unknown. Here, we present the results of molecular dynamics computations, supplemented by a bioinformatics analysis, that clarify the early stages of their catalytic cycle. We have elucidated the intricate binding mechanism of NADPH and L‐Orn to a class B monooxygenase, the ornithine hydroxylase from known as SidA. Our investigation involved a comprehensive characterization of the conformational changes associated with the FAD (Flavin Adenine Dinucleotide) cofactor, transitioning from theoutto theinposition. Furthermore, we explored the rotational dynamics of the nicotinamide ring of NADPH, shedding light on its role in facilitating FAD reduction, supported by experimental evidence. Finally, we also analyzed the extent of conservation of two Tyr‐loops that play critical roles in the process.

    

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5. Flavin-dependent halogenases catalyze enantioselective olefin halocyclization

   https://doi.org/10.1038/s41467-021-23503-3  

   Mondal, Dibyendu ; Fisher, Brian F. ; Jiang, Yuhua ; Lewis, Jared C. ( December 2021 , Nature Communications)

   null (Ed.)

   Abstract Halocyclization of alkenes is a powerful bond-forming tool in synthetic organic chemistry and a key step in natural product biosynthesis, but catalyzing halocyclization with high enantioselectivity remains a challenging task. Identifying suitable enzymes that catalyze enantioselective halocyclization of simple olefins would therefore have significant synthetic value. Flavin-dependent halogenases (FDHs) catalyze halogenation of arene and enol(ate) substrates. Herein, we reveal that FDHs engineered to catalyze site-selective aromatic halogenation also catalyze non-native bromolactonization of olefins with high enantioselectivity and near-native catalytic proficiency. Highly selective halocyclization is achieved by characterizing and mitigating the release of HOBr from the FDH active site using a combination of reaction optimization and protein engineering. The structural origins of improvements imparted by mutations responsible for the emergence of halocyclase activity are discussed. This expansion of FDH catalytic activity presages the development of a wide range of biocatalytic halogenation reactions. 

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