2015
DOI: 10.1021/jacs.5b03836
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Catalytic Mechanism of Cofactor-Free Dioxygenases and How They Circumvent Spin-Forbidden Oxygenation of Their Substrates

Abstract: Dioxygenases catalyze a diverse range of biological reactions by incorporating molecular oxygen into organic substrates. Typically, they use transition metals or organic cofactors for catalysis. Bacterial 1-H-3-hydroxy-4-oxoquinaldine-2,4-dioxygenase (HOD) catalyzes the spin-forbidden transfer of dioxygen to its N-heteroaromatic substrate in the absence of any cofactor. We combined kinetics, spectroscopic and computational approaches to establish a novel reaction mechanism. The present work gives insight into … Show more

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Cited by 80 publications
(153 citation statements)
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“…Catalysis could alternatively involve formation of a triplet state di-radical adduct between the singlet substrate and triplet O 2 . Recent experimental and computational evidence suggested that the anion of the substrate for HOD reacts directly with O 2 to form such an intermediate in a step that limits the overall reaction rate (22). In investigating the O 2 reactivity of NMO, we found that, consistent with the flavoenzyme paradigm, the reaction between dithranol and O 2 occurs as a slow step (Fig.…”
Section: Discussionsupporting
confidence: 65%
See 1 more Smart Citation
“…Catalysis could alternatively involve formation of a triplet state di-radical adduct between the singlet substrate and triplet O 2 . Recent experimental and computational evidence suggested that the anion of the substrate for HOD reacts directly with O 2 to form such an intermediate in a step that limits the overall reaction rate (22). In investigating the O 2 reactivity of NMO, we found that, consistent with the flavoenzyme paradigm, the reaction between dithranol and O 2 occurs as a slow step (Fig.…”
Section: Discussionsupporting
confidence: 65%
“…We have compared the properties of the reaction in both the presence and absence of the enzyme to understand how the latter contributes to catalysis. Finally, we have interpreted the results in light of mechanistic work with IsdG (from Staphylococcus aureus) (21) and the emerging model for catalysis by the increasingly well characterized cofactor-independent oxygenase, (1H)-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase (HOD) (4,(22)(23)(24)(25)(26)(27).…”
mentioning
confidence: 99%
“…A remarkable group of cofactor-independent oxygenases have been described which require neither an organic cofactor nor a metal to catalyze the incorporation of (di)oxygen into a single molecule of an organic substrate (18,19). Establishment of the catalytic mechanisms for this group of enzymes provides interesting mechanistic insights into substrate-assisted oxygen activation (20,21).…”
mentioning
confidence: 99%
“…Calculations were performed in Gaussian-09 [87], using density functional theory methods that have been calibrated and benchmarked against experimental rate constants previously [88][89][90][91]. In general, the UB3LYP [92,93] hybrid density functional was used for all calculations.…”
Section: Methodsmentioning
confidence: 99%