CHAPTER 37: Riboflavin and β-oxidation Flavoenzymes

Riboflavin, or vitamin B₂, is the biological precursor of the essential redox cofactors FAD and FMN, which are synthesised upon dietary intake of the vitamin. The unique physical and chemical properties of these flavins make them extremely versatile protein cofactors. When inserted into proteins, flavins afford a broad range of redox reactions and catalytic properties. In this chapter we focus on the interplay between flavoproteins involved in mitochondrial beta-oxidation and vitamin B₂ metabolism, especially in what concerns the protein functional and structural consequences of increased flavin levels in this organelle, subsequently to high-dose riboflavin intake. The latter aspect is particularly relevant in the context of inborn errors of metabolism affecting beta-oxidation and amino acid catabolism enzymes, frequently a consequence of missense mutations, which result in protein misfolding or catalytic impairment. We provide an overview of recent reports establishing that therapeutic intake of vitamin B₂ increases cellular flavin concentrations, thus modulating the levels of several proteins involved on this pathway by rescuing function, and we discuss the molecular and structural rationale for these effects. Ultimately, we describe a mechanistic scenario pinpointing the role exerted by flavins as protein folding helpers.