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Views: 220 Author: tcchems Publish Time: 2025-07-21 Origin: Site
Content Menu
● Introduction to Flavins and 5-Deazaflavin
● Structural Differences Between 5-Deazaflavin and Flavin
>> H2: Core Molecular Differences
>> H3: Impact on Redox Centers and Hydrogen Transfer
● Functional Differences: Redox Behavior and Radical Stability
>> H2: Electron Transfer Capacities
>> H3: Radical Stability and Dimer Formation
● Implications on Enzymatic and Catalytic Functions
>> H2: Loss of Electron Transfer and Oxygen Activation
>> H3: New Catalytic Behavior – Hydride Transfer and Nucleophilic Addition
● Biosynthesis and Chemical Synthesis of 5-Deazaflavin Derivatives
● Comparative Summary: 5-Deazaflavin vs Flavin
● Applications and Research Importance
● Challenges and Future Perspectives
● Frequently Asked Questions (FAQs)
Flavins are essential molecules that function as redox cofactors in a wide array of biological processes, including enzymatic electron transfer and catalysis. Among flavin analogs, 5-deazaflavin stands out due to its unique structural modification and distinct functional behavior. This article explores the key structural and functional differences between 5-deazaflavin and natural flavin, uncovering the biochemical and mechanistic implications of this difference in fields ranging from enzymology to bioorganic chemistry.
Flavins, such as flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), are derived from riboflavin (vitamin B2) and play pivotal roles in biological redox reactions. Their isoalloxazine ring system facilitates electron transfer reactions and activation of molecular oxygen.
5-Deazaflavin is a synthetic analog of flavin where the nitrogen atom at the 5-position of the isoalloxazine ring is replaced by a carbon atom (CH group). This seemingly modest structural change leads to profound functional differences, influencing redox properties, reactivity, and the mechanism of electron transfer.
The principal structural distinction is the substitution of the nitrogen at the 5-position in natural flavins with a carbon atom in 5-deazaflavin. This alteration affects the electronic distribution and hydrogen bonding capabilities of the molecule.
- Flavin Structure: Contains a central pyridine-type nitrogen at C-5 that participates in electron delocalization and stabilization of radicals.
- 5-Deazaflavin Structure: Replacement of the N-5 by a CH group excludes the ability to form the same hydrogen bonds and alters electronic resonance within the ring system.
This substitution renders 5-deazaflavin more similar in shape to a nicotinamide moiety but with different electronic characteristics.
Studies using nuclear magnetic resonance (NMR) have shown that in 5-deazaflavin, the C-5 position becomes the critical locus for hydrogen transfer during redox reactions, unlike natural flavins where the nitrogen plays a key role.
Reduction of 5-deazaflavin yields a species identified as 1,5-dihydro-5-deazaflavin, which is more stable than might be expected but possesses different reactivity patterns when compared to reduced flavin species.
Natural flavins are known for their ability to participate in both one-electron and two-electron redox reactions. A hallmark of flavins is the formation of flavin semiquinone radicals, which are crucial intermediates in many flavoprotein catalytic cycles.
In contrast, 5-deazaflavin radicals exhibit different chemical behavior:
- Upon one-electron reduction, 5-deazaflavin forms a short-lived radical species (1-HdFl) that acts as a strong reductant.
- This radical is unstable and decays by prototropy and dismutation but can be reversed by illumination.
Unlike natural flavins, the 5-deazaflavin radical does not support the double one-electron oxidation-reduction (oxidoreduction) cycles characteristic of flavosemiquinones, indicating a fundamental shift in redox mechanism.
Under prolonged illumination, 5-deazaflavin radicals form a covalent, photo-stable sigma-dimer via the C-5 carbon atoms, a process not observed with typical flavin radicals. This dimer formation is reversible by light and can modulate the availability of the radical form.
This dimerization reflects the altered radical stability stemming from the C-5 substitution and signifies a distinctive pathway for radical decay in 5-deazaflavins compared to natural flavins.
The replacement of N-5 with carbon in 5-deazaflavin results in the loss of two major activities generally attributed to flavins:
1. Electron Transfer: The intrinsic redox potential and radical stability necessary for electron shuttling in enzymes are diminished.
2. Dioxygen Activation: The capability of natural flavins to activate molecular oxygen for oxidative processes is abolished.
Despite losing these functions, 5-deazaflavin retains the ability for transhydrogenation reactions to some extent, highlighting a selective catalytic activity preservation.
5-Deazaflavin behaves more like a hydride transfer catalyst, similar in concept to nicotinamide coenzymes, fitting sterically into flavoprotein active sites but functioning through distinct mechanistic routes.
It favors:
- Nucleophilic substrate addition, particularly involving carbanion transfer.
- Formation of covalent intermediate sigma-adducts during photoreductions and electron transfer processes.
These capabilities provide a novel mechanistic insight and suggest why 5-deazaflavin analogs can serve as valuable mechanistic probes for understanding flavin-dependent catalysis.
The enzymatic synthesis of 5-deazaflavin derivatives such as 5-deazariboflavin 5′-phosphate and 5'-diphosphate (analogous to FMN and FAD) has been successfully achieved. Enzymes like partially purified FAD synthetase from *Brevibacterium ammoniagenes* convert riboflavin analogues directly to 5-deazaflavin cofactors at the dinucleotide level, enabling biochemical applications and studies.
Chemical reduction of 5-deazaflavin to the 1,5-dihydro form stabilizes it against autoxidation, thereby enhancing its utility in research settings aiming at elucidating flavin-related enzymatic mechanisms.
| Feature | Flavin | 5-Deazaflavin |
|---|---|---|
| Position 5 atom | Nitrogen (N) | Carbon (CH group) |
| Radical stability | Stable flavosemiquinone radicals | Radicals form short-lived species and reversible dimers |
| Redox reactions | Supports 1e- and 2e- transfers | Limited to hydride transfer and nucleophilic addition |
| Dioxygen activation | Present | Absent |
| Electron transfer in enzymes | Essential | Lost or significantly reduced |
| Catalytic activity | Electron transfer and oxygen activation | Hydride transfer, nucleophilic catalysis |
| Applications | Natural coenzymes in metabolism | Mechanistic probes, specialized catalysis |
Understanding 5-deazaflavin serves multiple scientific and practical purposes:
- Mechanistic Probes: Due to its unique electronic and catalytic profile, 5-deazaflavin is used to dissect flavin enzyme mechanisms, especially to distinguish electron transfer roles.
- Photochemical Studies: Its photo-stable dimers and reversible radical formation under light offer models to study flavin photochemistry.
- Design of Synthetic Catalysts: Insight into its distinct reactivity informs the design of novel coenzyme mimics and catalysts tailored for specific, non-natural redox reactions.
While 5-deazaflavin offers unmatched insight into flavin biochemistry, challenges remain in fully harnessing its potential:
- Achieving stable incorporation into functional enzymes.
- Extending understanding of its behavior in vivo.
- Developing new synthetic analogs with tailored properties derived from its unique reactivity.
These areas continue to attract research interest, promising new advances in enzymology and synthetic biology.
Q1: What is the main structural difference between flavin and 5-deazaflavin?
A1: 5-Deazaflavin replaces the nitrogen atom at the 5-position in flavin's isoalloxazine ring with a carbon atom, which dramatically changes its electron distribution and reactivity.
Q2: Does 5-deazaflavin participate in electron transfer like natural flavins?
A2: No, 5-deazaflavin radicals are less stable and do not mediate the typical one- and two-electron redox processes that natural flavins do; instead, they favor hydride transfer and nucleophilic addition.
Q3: How does the radical stability of 5-deazaflavin compare to flavin semiquinones?
A3: Flavin semiquinones are relatively stable radicals, while 5-deazaflavin radicals are short-lived, decaying via prototropy, dismutation, or forming reversible dimers under illumination.
Q4: What enzymatic activity is lost due to the 5-deaza substitution in flavin?
A4: The ability to activate molecular oxygen and perform electron transfer is lost; however, transhydrogenation activity is partially retained.
Q5: Why is 5-deazaflavin important in scientific research?
A5: It serves as a mechanistic probe to study flavoprotein catalysis, helping separate electron transfer functions from hydride transfer processes, thus enhancing understanding of enzyme mechanisms.
[1] https://pubmed.ncbi.nlm.nih.gov/6894393/
[2] https://pubmed.ncbi.nlm.nih.gov/3206/
[3] https://2024.sci-hub.se/2362/66c5ac23b2f2601112b94080ecf704fc/goldberg1981.pdf
[4] https://www.periodicos.capes.gov.br/index.php/acervo/buscador.html?task=detalhes&id=W2076420632
[5] https://deepblue.lib.umich.edu/bitstream/handle/2027.42/65939/j.1432-1033.1979.tb12952.x.pdf;sequence=1
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[8] https://www.semanticscholar.org/topic/Flavins/6602
[9] https://www.sciencedirect.com/science/article/abs/pii/0304416581904876
[10] https://patents.google.com/patent/CN102471283A/en
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