Abstract
Inborn errors of Riboflavin (Rf) transport and metabolism have been recently related to severe human neuromuscular disorders, as resulting in profound alteration of human flavoproteome and, therefore, of cellular bioenergetics. This explains why the interest in studying the “flavin world”, a topic which has not been intensively investigated before, has increased much over the last few years. This also prompts basic questions concerning how Rf transporters and FAD (flavin adenine dinucleotide) -forming enzymes work in humans, and how they can create a coordinated network ensuring the maintenance of intracellular flavoproteome. The concept of a coordinated cellular “flavin network”, introduced long ago studying humans suffering for Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), has been, later on, addressed in model organisms and more recently in cell models. In the frame of the underlying relevance of a correct supply of Rf in humans and of a better understanding of the molecular rationale of Rf therapy in patients, this review wants to deal with theories and existing experimental models in the aim to potentiate possible therapeutic interventions in Rf-related neuromuscular diseases.
Highlights
Inborn errors of Riboflavin (Rf) transport and metabolism have been recently related to severe human neuromuscular disorders, as resulting in profound alteration of human flavoproteome and, of cellular bioenergetics
Riboflavin (Rf, known as vitamin B2), a water-soluble vitamin belonging to the B-group vitamins, is the precursor of flavin cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which allow for cellular flavoproteome to become enzymatically active
Given the importance of vitamin B2 in oxidative metabolism crucial for nervous system economy, the mechanisms of Rf transport and homeostasis in the nervous system have been long investigated in the past and further clarified on the discovery of the human hRFVT2, which immediately appeared to be maximally expressed in the human brain and spinal cord [28,93]
Summary
Riboflavin (Rf, known as vitamin B2), a water-soluble vitamin belonging to the B-group vitamins, is the precursor of flavin cofactors FMN (flavin mononucleotide) and FAD (flavin adenine dinucleotide), which allow for cellular flavoproteome to become enzymatically active. The role of flavin cofactors in the enzymatic catalysis lies essentially in transferring reduction equivalents, giving rise to the semi-reduced or fully-reduced forms, FMN and FAD are essential molecular constituents of a large number of dehydrogenases, reductases and oxidases, mainly located in mitochondria, being involved in intermediary and terminal energetic metabolism of fatty acids, carbohydrates, amino acids, pyridoxine and choline [2]. In the majority of cases, apo-flavoenzymes bind flavin cofactors non-covalently (90%), whereas in redox homeostasis in both generating and scavenging reactive oxygen species (ROS) and reactive in some cases, a covalent linkage occurs. FAD-dependent oxidases play some roles in chromatin remodeling and epigenetic events, controlling the expression of genes involved in energy metabolism [17,18]. Rf has a central role in pyridoxine metabolism [19], in folate and Vitamin B12 recycling [20,21,22] and in one-carbon metabolisms, as well as in biosynthesis and regulation of coenzyme A, coenzyme Q10 , heme, steroids and thyroxine [23]
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