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Mechanism of Ultrafast Flavin Photoreduction in the Active Site of Flavoenzyme LSD1 Histone Demethylase
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Edité par CCSD ; The Royal Society of Chemistry -
International audience. Photoreduction of oxidized flavins has a functional role in photocatalytic and photoreceptor flavoproteins. In flavoproteins without light-dependent physiological functions, ultrafast, reversible flavin photoreduction is supposedly photoprotective by nature, and holds potential for nonnatural photocatalytic applications. In this work, we combine protein mutagenesis, ultrafast spectroscopy, molecular dynamics simulations and quantum mechanics calculations to investigate the nonfunctional flavin photoreduction in a flavoenzyme, lysine-specific demethylase 1 (LSD1) which is pivotal in DNA transcription. LSD1 harbors an oxidized flavin adenine dinucleotide (FAD) cofactor and multiple electron-donating residues in the active site. Upon photoexcitation, the FAD cofactor is photoreduced in < 200 fs by electron transfer (ET) from nearby residue(s), and the charge pairs recombine in ca. 2 ps. Site-directed mutagenesis pinpoints a specific tryptophan residue, W751, as the primary electron donor, whereas a tyrosine residue, Y761, despite being located closer to the flavin ring, does not effectively contribute to the process. Based on a hybrid quantum–classical computational approach, we characterize the W751–FAD and Y761–FAD charge-transfer states (CTW751 and CTY761, respectively), as well as the FAD locally excited state (LEFAD), and demonstrate that the coupling between LEFAD and CTW751 is larger than those involving CTY761 by an order of magnitude, rationalizing the experimental observations. More generally, this work highlights the role of the intrinsic protein environment and details of donor–acceptor molecular configurations on the dynamics of short-range ET involving a flavin cofactor and amino acid residue(s).
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