The human flavoproteome

Abstract

Vitamin B2 (riboflavin) is an essential dietary compound used for the enzymatic biosynthesis of FMN and FAD. The human genome contains 90 genes encoding for flavin-dependent proteins, six for riboflavin uptake and transformation into the active coenzymes FMN and FAD as well as two for the reduction to the dihydroflavin form. Flavoproteins utilize either FMN (16%) or FAD (84%) while five human flavoenzymes have a requirement for both FMN and FAD. The majority of flavin-dependent enzymes catalyze oxidation-reduction processes in primary metabolic pathways such as the citric acid cycle, β-oxidation and degradation of amino acids. Ten flavoproteins occur as isozymes and assume special functions in the human organism. Two thirds of flavin-dependent proteins are associated with disorders caused by allelic variants affecting protein function. Flavin-dependent proteins also play an important role in the biosynthesis of other essential cofactors and hormones such as coenzyme A, coenzyme Q, heme, pyridoxal 5'-phosphate, steroids and thyroxine. Moreover, they are important for the regulation of folate metabolites by using tetrahydrofolate as cosubstrate in choline degradation, reduction of N-5.10-methylenetetrahydrofolate to N-5-methyltetrahydrofolate and maintenance of the catalytically competent form of methionine synthase. These flavoenzymes are discussed in detail to highlight their role in health and disease.

Graphical abstract

Fig. 1

Flavin-catalyzed reactions connected to folate metabolism: dimethlyglycine dehydrogenase (EC 1.5.99.1, DMGDH), sarcosine dehydrogenase (EC 1.5.99.2, SARDH), N-5,10-methylene-tetrahydrofolate reductase (EC 1.5.1.20, MTHFR) and methionine synthase reductase (EC 1.16.1.8, MSR). Structures depicted are from the human methionine synthase reductase (2qtl) as well as the N-5,10-methylene-tetrahydrofolate reductase from Thermus thermophilus HB8 (3apt).

Fig. 2

The penultimate reaction in heme biosynthesis involves the six-electron oxidation of protoporphyrinogen-IX to protoporphyrin-IX by the FAD-dependent protoporphyrinogen-IX oxidase (EC 1.3.3.4, PPOX) (human structure: 3nks).

Fig. 3

Oxidation of pyridoxamine and pyridoxine 5′-phosphate to pyridoxal 5′-phosphate by the FMN-dependent pyridoxamine/pyridoxine 5′-phosphate oxidase (EC 1.4.3.5, PNPO), the last step of the PLP-biosynthesis. The structure shown is that of the human enzyme (1nrg).

Fig. 4

Decarboxylation of N-[(R)-4′-phosphopantothenoyl]-L-cysteine to pantotheine 4′-phosphate by the FMN-dependent 4′-phosphopantothenoylcysteine decarboxylase (EC 4.1.1.36, PPCDC). The structure shown is that of the human enzyme (1qzu).

Fig. 5

Hydroxylation of the ubiquinone precursors in 5-position of the aromatic system by COQ6 (EC 1.14.99.-). In yeast, the electrons required for reduction of dioxygen are supplied by an NADPH-dependent ferredoxin reductase-ferredoxin system.

Fig. 6

Reactions of the two FAD-dependent enzymes in cholesterol biosynthesis. The reaction shown on top involves the insertion of an oxygen atom (blue circle) by SQLE (EC 1.14.13.132) and the reaction shown on the bottom the reduction of the side chain double bond (green circle) by DHCR24 (EC 1.3.1.72).

Fig. 7

Role of DUOX1 and 2 in the biosynthesis of thyroxine. The iodination of tyrosine residues and the coupling of two iodinated tyrosines require hydrogen peroxide, which is provided by the oxidation of reduced FAD with molecular dioxygen.

Fig. 8

Dehalogenation of iodotyrosine catalyzed by IYD. The mono- and diiodotyrosine residues released from thyroglobulin are substrates of the enzyme. Reductively released iodine is then reused by thryoperoxidase for incorporation into tyrosine residues of thyroglobulin.