Flavin Coenzymes

Abstract

Flavins are yellow chromophores in organisms ranging from bacteria to humans and essential for practically all metabolic processes. They occur in nature in a variety of forms. The core of the flavin cofactor is the (iso)alloxazine nucleus with the most common forms as flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). A number of flavin cofactors are covalently linked to their apoproteins. The covalent linkage is, in general, via a modification of the benzene subnucleus and functional groups of amino acid side chains. As cofactors, flavins are distinguished by their ability to catalyse a wide variety of different processes. These include oxidation/reduction (redox) reactions, the activation of dioxygen, electron transfer, photo(bio)chemistry, the emission of light, reactions such as rearrangements not involving apparent, net redox steps, regulation processes and structural roles.

Key Concepts:

  • A salient property of the flavin cofactor core is its ability to catalyse a vast variety of chemical reactions.

  • Chemical variation of a basic molecule (the isoalloxazine) leads to several (modified) coenzymes that can differ significantly in their catalytic properties.

  • The type and position of the modification is a key determinant for the properties of the (modified) coenzyme.

  • Modified cofactors can be used – upon substitution of the native cofactor – to study the mechanisms of the catalysed reactions.

  • The cofactor interacts with the protein in many different ways. These, in turn, affect the properties of the cofactor as a catalyst. The result is a disparate selection of catalytic functions.

  • The flavin has – depending on its redox and ionisation state – characteristic spectral properties (both with respect to absorbance and fluorescence). These are conveniently employed to analyse the different species, their properties and conversions.

Keywords: FMN; FAD; flavoprotein; alloxazine; cofactor; redox

Figure 1.

Structure and nomenclature of flavins and analogues.

Figure 2.

Structures of naturally occurring modified flavins. With the exception of 5‐deazaflavins [XI] the residue (R) at N(10) is a ribityl that might be modified at its terminal end as shown in Figure . [VIII] carries a covalent linkage from the flavin C8 α‐methylene position to a protein functional group such as His‐N(3), His‐N(1), Tyr‐O or Cys‐S. In [IX] a Cys sulfur is linked to the flavin position C(6). In [IXa] the flavin is linked both to a Cys sulfur to position C(6) and to a His‐N(1) of the protein backbone. In [X] the modification is at the benzene C(8) position. [XI] is the chromophore of 8‐hydroxy‐5‐deazaflavins, which additionally carry a modified N(10) side chain R. In [XII] the N(10)‐ribityl side chain carries further modifications.

Figure 3.

Outline of the most used pathway for the chemical synthesis of the flavin nucleus. [XIII] is a xylidine derivative and [XIV] a barbituric acid.

Figure 4.

Outline of the biosynthesis of riboflavin [III]. The origin of the components of the xylene ring is denoted in shading in the 8‐ribityllumazine [XVI] precursor.

Figure 5.

Absorption spectra of the flavin molecule [III] in its different redox states and ionic forms. Note that the semiquinone forms (radical forms) can be stabilised to nearly 100% only when bound to enzymes such as glucose oxidase. The anionic form of free reduced flavin does not show major differences compared to the neutral one in the visible range.

Figure 6.

Redox and ionisation states of the flavin.

Figure 7.

Functions and classes of reactions catalysed by flavoenzymes.

Figure 8.

Possible configurations of flavins. The ‘hairpin’ configuration preferred by free FAD in solution is shown on the top. The bottom structure shows the reduced flavin viewed along its N(5)–C(10) axis, along which it can ‘bend’.

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References

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Further Reading

Chapman SK and Reid GA (eds) (1998) Flavoprotein Protocols, pp. 1–9. (A recent collection of methods applicable to various problems in the context of flavin biochemistry.) Totowa: Humana Press.

Chytill F and McCormick DB (eds) (1986) Vitamins and Coenzymes Part G. Methods in Enzymology, vol. 122. San Diego, CA: Academic Press.

Chytill F and McCormick DB (eds) (1986) Vitamins and Coenzymes Part H. Methods in Enzymology, vol. 123. San Diego, CA: Academic Press.

Flavins and Flavoproteins (1965) A Series of Symposium Proceedings of the International Congress on Flavins and Flavoproteins held every three years since their Inception in 1965. No Volume was Published for the 1972 Symposium.

Hille R, Miller SM and Palfrey B (eds) (2013) Handbook of Flavoproteins vols 1 and 2. Berlin/Boston: W de Gruyter GmbH.

McCormick DB, Suttie JW and Wagner C (eds) (1997a) Vitamins and Coenzymes Part I. Methods in Enzymology, vol. 279. San Diego, CA: Academic Press.

McCormick DB, Suttie JW and Wagner C (eds) (1997b) Vitamins and Coenzymes Part J. Methods in Enzymology, vol. 280. San Diego, CA: Academic Press.

McCormick DB, Suttie JW and Wagner C (eds) (1997c) Vitamins and Coenzymes Part K. Methods in Enzymology, vol. 281. San Diego, CA: Academic Press.

McCormick DB and Wright LD (eds) (1970) Vitamins and Coenzymes. Methods in Enzymology, vol. 18A. San Diego, CA: Academic Press.

McCormick DB and Wright LD (eds) (1971) Vitamins and Coenzymes. Methods in Enzymology, vols 18A and 18C. San Diego, CA: Academic Press.

McCormick DB and Wright LD (eds) (1979) Vitamins and Coenzymes Part D. Methods in Enzymology, vol. 62. San Diego, CA: Academic Press.

McCormick DB and Wright LD (eds) (1980) Vitamins and Coenzymes Part E. Methods in Enzymology, vol. 66. San Diego, CA: Academic Press.

McCormick DB and Wright LD (eds) (1980) Vitamins and Coenzymes Part F. Methods in Enzymology, vol. 67. San Diego, CA: Academic Press.

Müller F (1991) Chemistry and Biochemistry of Flavoenzymes, vol. 3. Boca Raton, FL: CRC Press.

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Ghisla, Sandro, and Edmondson, Dale E(Sep 2014) Flavin Coenzymes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000654.pub3]