A single hydrogen bond that tunes flavin redox reactivity and activates it for modification

Das, Debarati; Miller, Anne-Frances

doi:10.1039/d4sc01642d

Chem. Sci.

2024

DOI: 10.1039/d4sc01642d

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A single hydrogen bond that tunes flavin redox reactivity and activates it for modification

Debarati Das,

Anne-Frances Miller

Abstract: A hydrogen bond from a conserved histidine tunes flavin reactivity in favour of a catalytically critical anionic semiquinone state (front). However it also favours an electronically similar anionic methide intermediate (back) leading to flavin modification.

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New Electron-Transfer Chain to a Flavodiiron Protein in Fusobacterium nucleatum Couples Butyryl-CoA Oxidation to O₂ Reduction

Bystrom,

Wolthers

2024

Biochemistry

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Fusobacterium nucleatum, a Gram-negative obligate anaerobe, is common to the oral microbiota, but the species is known to infect other sites of the body where it is associated with a range of pathologies. At present, little is known about the mechanisms by which F. nucleatum mitigates against oxidative and nitrosative stress. Inspection of the F. nucleatum subsp. polymorphum ATCC 10953 genome reveals that it encodes a flavodiiron protein (FDP; FNP2073) that is known in other organisms to reduce NO to N 2 O and/or O 2 to H 2 O. FNP2073 is dicistronic with a gene encoding a multicomponent enzyme termed BCR for butyryl-CoA reductase. BCR is composed of a butyryl-CoA dehydrogenase domain (BCD), the C-terminal domain of the α-subunit of the electron-transfer flavoprotein (Etfα), and a rubredoxin domain. We show that BCR and the FDP form an α 4 β 4 heterotetramic complex and use butyryl-CoA to selectively reduce O 2 to H 2 O. The FAD associated with the Etfα domain (α-FAD) forms red anionic semiquinone (FAD •− ), whereas the FAD present in the BCD domain (δ-FAD) forms the blue-neutral semiquinone (FADH • ), indicating that both cofactors participate in one-electron transfers. This was confirmed in stopped-flow studies where the reduction of oxidized BCR with an excess of butyryl-CoA resulted in rapid (<1.6 ms) interflavin electron transfer evidenced by the formation of the FAD •− . Analysis of bacterial genomes revealed that the dicistron is present in obligate anaerobic gut bacteria considered to be beneficial by virtue of their ability to produce butyrate. Thus, BCR-FDP may help to maintain anaerobiosis in the colon.

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New Electron-Transfer Chain to a Flavodiiron Protein in Fusobacterium nucleatum Couples Butyryl-CoA Oxidation to O₂ Reduction

Bystrom,

Wolthers

2024

Biochemistry

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Polar Interactions between Substrate and Flavin Control Iodotyrosine Deiodinase Function

Lemen,

Rokita

2024

Biochemistry

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A single hydrogen bond that tunes flavin redox reactivity and activates it for modification

Abstract: A hydrogen bond from a conserved histidine tunes flavin reactivity in favour of a catalytically critical anionic semiquinone state (front). However it also favours an electronically similar anionic methide intermediate (back) leading to flavin modification.

Cited by 2 publications

References 58 publications

New Electron-Transfer Chain to a Flavodiiron Protein in Fusobacterium nucleatum Couples Butyryl-CoA Oxidation to O₂ Reduction

New Electron-Transfer Chain to a Flavodiiron Protein in Fusobacterium nucleatum Couples Butyryl-CoA Oxidation to O₂ Reduction

Polar Interactions between Substrate and Flavin Control Iodotyrosine Deiodinase Function

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A single hydrogen bond that tunes flavin redox reactivity and activates it for modification

Abstract: A hydrogen bond from a conserved histidine tunes flavin reactivity in favour of a catalytically critical anionic semiquinone state (front). However it also favours an electronically similar anionic methide intermediate (back) leading to flavin modification.

Cited by 2 publications

References 58 publications

New Electron-Transfer Chain to a Flavodiiron Protein in Fusobacterium nucleatum Couples Butyryl-CoA Oxidation to O2 Reduction

New Electron-Transfer Chain to a Flavodiiron Protein in Fusobacterium nucleatum Couples Butyryl-CoA Oxidation to O2 Reduction

Polar Interactions between Substrate and Flavin Control Iodotyrosine Deiodinase Function

Contact Info

Product

Resources

About

New Electron-Transfer Chain to a Flavodiiron Protein in Fusobacterium nucleatum Couples Butyryl-CoA Oxidation to O₂ Reduction

New Electron-Transfer Chain to a Flavodiiron Protein in Fusobacterium nucleatum Couples Butyryl-CoA Oxidation to O₂ Reduction