Flavin-Dependent Enzymatic Catalysis in Biochemical Systems

Flavin-dependent enzymes constitute a versatile class of biocatalysts that employ isoalloxazine cofactors—flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN)—to mediate a wide array of redox transformations. These enzymes are central to primary metabolism, secondary metabolite biosynthesis and detoxification pathways, orchestrating reactions such as hydroxylation, monooxygenation, dehalogenation, sulphur oxidation and radical-mediated rearrangements. Structurally, flavin‐dependent systems are divided into single-component monooxygenases, which bind both flavin and substrate within one polypeptide, and two-component systems in which a reductase supplies reduced flavin to an oxygenase module. The catalytic cycle typically proceeds via reduction of the flavin cofactor by NAD(P)H, reaction with molecular oxygen to form a reactive C4a-hydroperoxyflavin intermediate, and subsequent substrate oxidation. Conformational gating of the flavin ring, coupled proton‐electron transfers and precise active‐site coordination enable these enzymes to stabilise transient intermediates and achieve high chemo-, regio- and stereoselectivity. Beyond their fundamental roles in biology, flavoenzymes have attracted intense interest as sustainable biotechnological tools for fine chemical and pharmaceutical production, environmental bioremediation and photoresponsive applications. Recent advances in structural biology, protein engineering and cofactor manipulation continue to expand the repertoire of flavin-dependent catalysis, underscoring its global significance and practical utility.

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Flavin-Dependent Enzymatic Catalysis in Biochemical Systems publication trend

The graph below shows the total number of articles in flavin-dependent enzymatic catalysis in biochemical systems across all publications each year (not limited to Nature Index journals).

Technical terms

Flavoenzyme: An enzyme that utilises a flavin cofactor (FAD or FMN) to mediate redox reactions.

Flavin Adenine Dinucleotide (FAD): A redox‐active cofactor consisting of an isoalloxazine ring linked to adenine dinucleotide, central to many oxidoreductases.

Flavin Mononucleotide (FMN): A phosphorylated form of riboflavin serving as a prosthetic group in various flavoenzymes.

Monooxygenase: An enzyme that incorporates one atom of molecular oxygen into substrate while reducing the second atom to water.

C4a-Hydroperoxyflavin: A key reactive intermediate formed when reduced flavin reacts with O₂, capable of transferring an oxygen atom to substrates.

Pummerer Rearrangement: A chemical transformation involving activation of a sulfoxide, here catalysed by an enzyme to cleave C–S bonds via a rearrangement mechanism.

References

1. Alkylcysteine Sulfoxide C–S Monooxygenase Uses a Flavin-Dependent Pummerer Rearrangement. Journal of the American Chemical Society (2023).
2. Design and Synthesis of Artificial FAD Cofactors for the Light-Triggered Covalent Flavinylation of Flavoenzymes. ACS Catalysis (2024).
3. 4-Hydroxyphenylacetate 3-Hydroxylase (4HPA3H): A Vigorous Monooxygenase for Versatile O-Hydroxylation Applications in the Biosynthesis of Phenolic Derivatives. International Journal of Molecular Sciences (2024).
4. Flavoprotein monooxygenases: Versatile biocatalysts. Biotechnology Advances (2021).
5. Two-Component FAD-Dependent Monooxygenases: Current Knowledge and Biotechnological Opportunities. Biology (2018).
6. Activation of molecular oxygen by flavins and flavoproteins.. Journal of Biological Chemistry (1994).
7. Proton-Coupled Electron Transfer and Adduct Configuration Are Important for C4a-Hydroperoxyflavin Formation and Stabilization in a Flavoenzyme. Journal of the American Chemical Society (2013).