Special Issue: Flavins and Flavoproteins

Chaiyen, Pimchai; Scrutton, Nigel S.

doi:10.1111/febs.13337

“…Flavins and the physical and chemical principles by which they perform catalysis have been the subject of intensive research for >60 years. − A large part of the current understanding of the chemistries facilitated by flavoenzymes is based on seminal works performed in the 1970s–1980s by the teams of Thomas C. Bruice and Vincent Massey, which led to the current view of the reaction of reduced flavin with dioxygen in oxidases and monooxygenases. ,− A wealth of mechanistic, kinetic, structural, and computational data provide consistent clues about the molecular, functional, and structural properties of flavoprotein oxidases and oxygenases. Yet, not all aspects of flavoenzyme-catalyzed reactions have been solved.…”

Section: Introductionmentioning

confidence: 99%

Same Substrate, Many Reactions: Oxygen Activation in Flavoenzymes

Romero

¹

,

Castellanos

²

,

Gadda

³

et al. 2018

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Over time, organisms have evolved strategies to cope with the abundance of dioxygen on Earth. Oxygen-utilizing enzymes tightly control the reactions involving O mostly by modulating the reactivity of their cofactors. Flavins are extremely versatile cofactors that are capable of undergoing redox reactions by accepting either one electron or two electrons, alternating between the oxidized and the reduced states. The physical and chemical principles of flavin-based chemistry have been investigated widely. In the following pages we summarize the state of the art on a key area of research in flavin enzymology: the molecular basis for the activation of O by flavin-dependent oxidases and monooxygenases. In general terms, oxidases use O as an electron acceptor to produce HO, while monooxygenases activate O by forming a flavin intermediate and insert an oxygen atom into the substrate. First, we analyze how O reaches the flavin cofactor embedded in the protein matrix through dedicated access pathways. Then we approach O activation from the perspective of the monooxygenases, their preferred intermediate, the C(4a)-(hydro)peroxyflavin, and the cases in which other intermediates have been described. Finally, we focus on understanding how the architectures developed in the active sites of oxidases promote O activation and which other factors operate in its reactivity.

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“…[3][4][5] These interactions also modulate the flavin redox potential from −400 to 60 mV, allowing oxidation of a range of aliphatic and aromatic substrates. [6][7][8] Flavin redox reactions are an example of proton-coupled electron transfers or PCET, a broad family of reactions and energy conversion processes in chemistry. [9][10][11] PCET mechanisms are characterized by the number of electrons involved, such as in hydride (2e − /1H + ) versus hydrogen-atom (1e − /1H + , or HAT) transfer; 12 the order of steps or their concurrency, such as electron transfer first, proton second (ETPT) or concerted proton-electron transfer (CPET); 9,13 whether the transfers proceed from(to) the same or different chemical groups in the donor(acceptor), as in multiple-site PCET; 10,14 the tunneling behavior and the adiabacity or participation of excited-states in the transfer processes.…”

Section: Introductionmentioning

confidence: 99%

“…Enzymes equipped with flavin cofactors comprise the most abundant class of natural catalysts for combined proton and electron transfer. , The redox center in all natural flavins is formed by the heteronuclear tricyclic isoalloxazine ring (Figure ), primarily attached to the protein by noncovalent hydrogen bonds, stacking, and cation−π contacts. − These interactions also modulate the flavin redox potential from −400 to 60 mV, allowing oxidation of a range of aliphatic and aromatic substrates. − …”

Section: Introductionmentioning

confidence: 99%

Mechanisms for Flavin-Mediated Oxidation: Hydride or Hydrogen-Atom Transfer?

Curtolo

¹

,

Arantes

²

2020

J. Chem. Inf. Model.

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Flavins are versatile biological cofactors which catalyze proton-coupled electron transfers (PCET) with varying number and coupling of electrons. Flavin mediated oxidation of nicotinamide adenine dinucleotide (NADH) and of succinate, initial redox reactions in cellular respiration, were examined here with multiconfigurational quantum chemical calculations and a simple analysis of the wave-function proposed to quantify electron transfer along the proton reaction coordinate. The mechanism of NADH oxidation is a prototypical hydride transfer, with two electrons moving concerted with the proton to the same acceptor group. However, succinate oxidation depends on the elimination step and can proceed through the transfer of hydride or hydrogen-atom, with proton and electrons moving to different groups in both cases. These results help to determine the mechanism of fundamental but still debated biochemical reactions, and illustrate a new diagnostic tool for electron transfer that can be useful to characterize a broad class of PCET processes.

show abstract

“…[3][4][5] These interactions also modulate the flavin redox potential from −400 to 60 mV, allowing oxidation of a range of aliphatic and aromatic substrates. [6][7][8] Flavin redox reactions are an example of proton-coupled electron transfers or PCET, a broad family of reactions and energy conversion processes in chemistry. 9-11 PCET mechanisms are characterized by the number of electrons involved, such as in hydride (2e − /1H + ) versus hydrogen-atom (1e − /1H + , or HAT) transfer; 12 the order of steps or their concurrency, such as electron transfer first, proton second (ETPT) or concerted proton-electron transfer (CPET); 9,13 whether the transfers proceed from(to) the same or different chemical groups in the donor(acceptor), as in multiple-site PCET; 10,14 the tunneling behavior and the adiabacity or participation of excited-states in the transfer processes.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms for Flavin Mediated Oxidation: Hydride or Hydrogen-Atom Transfer?

Curtolo¹,

Arantes

²

2020

Preprint

0

View full text Add to dashboard Cite

Flavins are versatile biological cofactors which catalyze proton-coupled electron transfers (PCET) with varying number and coupling of electrons. Flavin mediated oxidation of nicotinamide adenine dinucleotide (NADH) and of succinate, initial redox reactions in cellular respiration, were examined here with multiconfigurational quantum chemical calculations and a simple analysis of the wave-function proposed to quantify electron transfer along the proton reaction coordinate. The mechanism of NADH oxidation is a prototypical hydride transfer, with two electrons moving concerted with the proton to the same acceptor group. However, succinate oxidation depends on the elimination step and can proceed through the transfer of hydride or hydrogen-atom, with proton and electrons moving to different groups in both cases. These results help to determine the mechanism of fundamental but still debated biochemical reactions, and illustrate a new diagnostic tool for electron transfer that can be useful to characterize a broad class of PCET processes. <br>

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Special Issue: Flavins and Flavoproteins

Cited by 6 publications

References 18 publications

Same Substrate, Many Reactions: Oxygen Activation in Flavoenzymes

Same Substrate, Many Reactions: Oxygen Activation in Flavoenzymes

Mechanisms for Flavin-Mediated Oxidation: Hydride or Hydrogen-Atom Transfer?

Mechanisms for Flavin Mediated Oxidation: Hydride or Hydrogen-Atom Transfer?

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