Riboflavin transport and metabolism in humans

Abstract

Recent studies elucidated how riboflavin transporters and FAD forming enzymes work in humans and create a coordinated flavin network ensuring the maintenance of cellular flavoproteome. Alteration of this network may be causative of severe metabolic disorders such as multiple acyl-CoA dehydrogenase deficiency (MADD) or Brown-Vialetto-van Laere syndrome. A crucial step in the maintenance of FAD homeostasis is riboflavin uptake by plasma and mitochondrial membranes. Therefore, studies on recently identified human plasma membrane riboflavin transporters are presented, together with those in which still unidentified mitochondrial riboflavin transporter(s) have been described. A main goal of future research is to fill the gaps still existing as for some transcriptional, functional and structural details of human FAD synthases (FADS) encoded by FLAD1 gene, a novel "redox sensing" enzyme. In the frame of the hypothesis that FADS, acting as a "FAD chaperone", could play a crucial role in the biogenesis of mitochondrial flavo-proteome, several basic functional aspects of flavin cofactor delivery to cognate apo-flavoenzyme are also briefly dealt with. The establishment of model organisms performing altered FAD homeostasis will improve the molecular description of human pathologies. The molecular and functional studies of transporters and enzymes herereported, provide guidelines for improving therapies which may have beneficial effects on the altered metabolism.

Disorders of riboflavin metabolism

“…Three human plasma membrane riboflavin transporters have been characterised (Figure A): RFVT1 (previously hRFT1), RFVT2 (hRFT3), and RFVT3 (hRFT2), encoded by SLC52A1 , SLC52A2 , and SLC52A3 , respectively . These three transporters have different subcellular locations and tissue specificities . Free riboflavin is transported into enterocytes via carrier‐mediated uptake by RFVT3, a saturable transport process at the apical membrane which is reported to be linear up to approximately 30 mg riboflavin per meal, and beyond which little additional absorption of riboflavin occurs …”

“…The question mark indicates that FADT‐mediated efflux of FAD from the mitochondrial matrix to the cytosol remains to be established. See also Barile et al (B) After cellular uptake of riboflavin, flavocoenzymes are formed by a sequential pathway involving riboflavin kinase and FAD synthase. Both steps require ATP.…”

“…After cellular uptake, riboflavin is quickly transformed into its catalytically active cofactors by the action of two enzymes: riboflavin kinase (RFK) (EC 2.7.1.26) and FAD synthase (FADS) (EC 2.7.7.2) which catalyse FMN and FAD production, respectively (Figure B). Riboflavin may be released into the portal blood and to the liver in its free form or as FMN after being transported by RFVT1 and RFVT2 which are embedded within the basolateral membrane of enterocytes . Circulating plasma riboflavin is bound to either albumin or immunoglobulins or is converted into its coenzyme forms in erythrocytes or leukocytes.…”

“…FADS catalyses the adenylation of FMN to FAD . In humans, distinct isoforms of this enzyme are distributed in different subcellular compartments and generated by alternative splicing of the FLAD1 gene . The most abundant of these isoforms, that is, the cytosolic enzyme or isoform 2, has been shown to be a bifunctional enzyme with both FADS and hydrolase activity .…”

An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency

“…Other important roles of flavoproteins include: the activation of other B class vitamins, redox homeostasis, transcriptional regulation through enzymatic chromatin modifications, caspase‐independent apoptosis, and cytoskeletal reorganization …”