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1. 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)

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2. New frontiers in flavin-dependent monooxygenases

   https://doi.org/10.1016/j.abb.2021.108765  

   Reis, Renata A.G.; Li, Hao; Johnson, Maxim; Sobrado, Pablo (March 2021, Archives of Biochemistry and Biophysics)

   null (Ed.)
3. Understanding flavin electronic structure and spectra

   https://doi.org/10.1002/wcms.1541  

   Kar, Rajiv K.; Miller, Anne‐Frances; Mroginski, Maria‐Andrea (May 2021, WIREs Computational Molecular Science)

   Abstract Flavins have emerged as central to electron bifurcation, signaling, and countless enzymatic reactions. In bifurcation, two electrons acquired as a pair are separated in coupled transfers wherein the energy of both is concentrated on one of the two. This enables organisms to drive demanding reactions based on abundant low‐grade chemical fuel. To enable incorporation of this and other flavin capabilities into designed materials and devices, it is essential to understand fundamental principles of flavin electronic structure that make flavins so reactive and tunable by interactions with protein. Emerging computational tools can now replicate spectra of flavins and are gaining capacity to explain reactivity at atomistic resolution, based on electronic structures. Such fundamental understanding can moreover be transferrable to other chemical systems. A variety of computational innovations have been critical in reproducing experimental properties of flavins including their electronic spectra, vibrational signatures, and nuclear magnetic resonance (NMR) chemical shifts. A computational toolbox for understanding flavin reactivity moreover must be able to treat all five oxidation and protonation states, in addition to excited states that participate in flavoprotein's light‐driven reactions. Therefore, we compare emerging hybrid strategies and their successes in replicating effects of hydrogen bonding, the surrounding dielectric, and local electrostatics. These contribute to the protein's ability to modulate flavin reactivity, so we conclude with a survey of methods for incorporating the effects of the protein residues explicitly, as well as local dynamics. Computation is poised to elucidate the factors that affect a bound flavin's ability to mediate stunningly diverse reactions, and make life possible. This article is categorized under:Structure and Mechanism > Computational Biochemistry and BiophysicsElectronic Structure Theory > Combined QM/MM MethodsTheoretical and Physical Chemistry > Spectroscopy 

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4. 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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5. Role of reduced flavin in dehalogenation reactions

   https://doi.org/10.1016/j.abb.2020.108696  

   Sobrado, Pablo (January 2021, Archives of Biochemistry and Biophysics)

   null (Ed.)