New insights into the nutritional genomics of adult-onset riboflavin-responsive diseases

Abstract

Riboflavin, or vitamin B2, is an essential nutrient that serves as a precursor to flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). The binding of the FAD and/or FMN cofactors to flavoproteins is critical for regulating their assembly and activity. There are over 90 proteins in the human flavoproteome that regulate a diverse array of biochemical pathways including mitochondrial metabolism, riboflavin transport, ubiquinone and FAD synthesis, antioxidant signalling, one-carbon metabolism, nitric oxide signalling and peroxisome oxidative metabolism. The identification of patients with genetic variants in flavoprotein genes that lead to adult-onset pathologies remains a major diagnostic challenge. However, once identified, many patients with adult-onset inborn errors of metabolism demonstrate remarkable responses to riboflavin therapy. We review the structure:function relationships of mutant flavoproteins and propose new mechanistic insights into adult-onset riboflavin-responsive pathologies and metabolic dysregulations that apply to multiple biochemical pathways. We further address the vexing issue of how the inheritance of genetic variants in flavoprotein genes leads to an adult-onset disease with complex symptomologies and varying severities. We also propose a broad clinical framework that may not only improve the current diagnostic rates, but also facilitate a personalized approach to riboflavin therapy that is low cost, safe and lead to transformative outcomes in many patients.

Metabolism of FAD, FMN and riboflavin (vitamin B2) in the human parasitic blood flukeSchistosoma mansoni

“…Figure 6A shows an alignment of the SmFADS protein with counterparts from S. haematobium and S. japonicum as well as homologs from a variety of other organisms. Similar to human and other eukaryotic FADS, SmFADS also contains two major domains: an N-terminal molybdenum cofactor (MoCF) binding domain (highlighted in yellow in figure 6A), and a C-terminal phosphoadenosine phosphosulphate (PAPS) domain (so called since it is also found in PAPS reductase enzymes and in PAPS sulphotransferases, highlighted in green in figure 6A) 31–33 . Highly conserved residues in the MoCF domain that are presumed to bind molybdopterin, are shown in blue and indicated with the # symbol (Fig.…”