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Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 71049

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Special Issue Editors

Prof. Michele Galluccio

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Guest Editor

Department DiBEST (Biologia, Ecologia, Scienze della Terra), Unity of Molecular Biology, University of Calabria, Via P. Bucci 6C, 87036 Arcavacata di Rende, Italy
Interests: protein expression and purification; structure function studies; FAD synthase isoforms; SLC transporters; enzymes
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Maria Barile

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Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari A. Moro, Via Orabona, 4, I-70126 Bari, Italy
Interests: Rf and derived cofactors; transport metabolism; cofactor assembly; related human disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Flavin-adenine-dinucleotide (FAD), derived from riboflavin (Rf; vitamin B2), is the ubiquitous cofactor of a number of flavoenzymes, most of which are involved in redox reactions. Several cellular processes depend on FAD, namely: metabolism, bioenergetics, protein folding, ROS production, as well as defense against oxidative stress, redox epigenetics, cell differentiation, and many others. Therefore, a fine coordination among apo-flavoprotein turn-over, cofactor availability, and, in eukaryotic cells, sub-cellular flavin trafficking, is required in order to ensure correct flavoproteome maintenance; in humans, an alteration in its regulation, in fact, leads to a number of pathological conditions, which, in some cases, are treatable with high doses of Rf.

Rf is essential for mammals. The biosynthesis of FAD, starting from extracellular Rf, requires the sequential action of specialized transporters (RFVTs), riboflavin kinase (RFK; EC 2.7.1.26), which catalyze the formation of FMN, and FAD synthase or FMN adenylyl transferase (FADS or FMNAT; EC 2.7.7.2), which adenylates FMN to FAD and ensures an adequate supply and the “on demand” delivery of the cofactor to nascent apo-flavoproteins. RFK and FADS are distinct polypeptides coded by rfk and flad1 genes, respectively. Different isoforms of FADS exist in humans, with different domain organization and subcellular localization; some of these isoforms, besides the transferase domain, present a module performing a FAD hydrolase activity.

Prokaryotes can either synthesize Rf or take it up from the outside, but they still necessitate synthesizing FMN and FAD, principally by using a single canonical bifunctional protein, which provides both RFK and FADS activities. The presence of both monofunctional RFK and FADS, as well as prokaryotic-like bifunctional enzymes, has been demonstrated in plants and in lower eukaryotes.

While the RFK domain is highly conserved along evolution, the FADS module and Rf translocators perform a profound structural specificity between prokaryotes and eukaryotes. Therefore, the enzymes involved in FAD forming can be potential targets for antimicrobial drugs.

The main goal of this Special Issue is to cover the molecular and functional aspects connected to cellular flavoproteome and its maintenance, looking for roles that go beyond the cellular metabolism in a comparative/evolutive overview of the biological world. In this scenario, different aspects of FAD homeostasis and delivery to nascent flavoproteins will be covered. Particular attention will be devoted to their alterations in human pathology, as emphasized by the recent discovery of RFVTs and FLAD1 as illness genes for human neuro-muscular disorders.

Dr. Michele Galluccio
Prof. Dr. Maria Barile
Guest Editors

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Keywords

riboflavin transporters
FAD
FMN
riboflavin
RFK
FADS
FLAD1
flavoenzymes

Published Papers (12 papers)

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Research

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16 pages, 3102 KiB

Open AccessArticle

Functional Recovery of a GCDH Variant Associated to Severe Deflavinylation—Molecular Insights into Potential Beneficial Effects of Riboflavin Supplementation in Glutaric Aciduria-Type I Patients

by Joana V. Ribeiro, Cláudio M. Gomes and Bárbara J. Henriques

Int. J. Mol. Sci. 2020, 21(19), 7063; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197063 - 25 Sep 2020

Cited by 4 | Viewed by 3085

Abstract

Riboflavin is the biological precursor of two important flavin cofactors—flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)—that are critical prosthetic groups in several redox enzymes. While dietary supplementation with riboflavin is a recognized support therapy in several inborn errors of metabolism, it has yet unproven benefits in several other pathologies affecting flavoproteins. This is the case for glutaric aciduria type I (GA-I), a rare neurometabolic disorder associated with mutations in the GCDH gene, which encodes for glutaryl-coenzyme A (CoA) dehydrogenase (GCDH). Although there are a few reported clinical cases that have responded to riboflavin intake, there is still not enough molecular evidence supporting therapeutic recommendation. Hence, it is necessary to elucidate the molecular basis in favor of riboflavin supplementation in GA-I patients. Here, using a combination of biochemical and biophysical methodologies, we investigate the clinical variant GCDH-p.Val400Met as a model for a phenotype associated with severe deflavinylation. Through a systematic analysis, we establish that recombinant human GCDH-p.Val400Met is expressed in a nonfunctional apo form, which is mainly monomeric rather than tetrameric. However, we show that exogenous FAD is a driver for structural reorganization of the mutant enzyme with concomitant functional recovery, improved thermolability, and resistance to trypsin digestion. Overall, these results establish proof of principle for the beneficial effects of riboflavin supplementation in GA-I patients. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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18 pages, 3486 KiB

Open AccessArticle

The Flavoproteome of the Model Plant Arabidopsis thaliana

by Patrick Schall, Lucas Marutschke and Bernhard Grimm

Int. J. Mol. Sci. 2020, 21(15), 5371; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155371 - 28 Jul 2020

Cited by 15 | Viewed by 3418

Abstract

Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are essential cofactors for enzymes, which catalyze a broad spectrum of vital reactions. This paper intends to compile all potential FAD/FMN-binding proteins encoded by the genome of Arabidopsis thaliana. Several computational approaches were applied to group the entire flavoproteome according to (i) different catalytic reactions in enzyme classes, (ii) the localization in subcellular compartments, (iii) different protein families and subclasses, and (iv) their classification to structural properties. Subsequently, the physiological significance of several of the larger flavoprotein families was highlighted. It is conclusive that plants, such as Arabidopsis thaliana, use many flavoenzymes for plant-specific and pivotal metabolic activities during development and for signal transduction pathways in response to biotic and abiotic stress. Thereby, often two up to several homologous genes are found encoding proteins with high protein similarity. It is proposed that these gene families for flavoproteins reflect presumably their need for differential transcriptional control or the expression of similar proteins with modified flavin-binding properties or catalytic activities. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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19 pages, 3144 KiB

Open AccessArticle

Flavin Adenine Dinucleotide Fluorescence as an Early Marker of Mitochondrial Impairment During Brain Hypoxia

by Nikolaus Berndt, Richard Kovács, Jörg Rösner, Iwona Wallach, Jens P. Dreier and Agustin Liotta

Int. J. Mol. Sci. 2020, 21(11), 3977; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113977 - 01 Jun 2020

Cited by 8 | Viewed by 3277

Abstract

Multimodal continuous bedside monitoring is increasingly recognized as a promising option for early treatment stratification in patients at risk for ischemia during neurocritical care. Modalities used at present are, for example, oxygen availability and subdural electrocorticography. The assessment of mitochondrial function could be an interesting complement to these modalities. For instance, flavin adenine dinucleotide (FAD) fluorescence permits direct insight into the mitochondrial redox state. Therefore, we explored the possibility of using FAD fluorometry to monitor consequences of hypoxia in brain tissue in vitro and in vivo. By combining experimental results with computational modeling, we identified the potential source responsible for the fluorescence signal and gained insight into the hypoxia-associated metabolic changes in neuronal energy metabolism. In vitro, hypoxia was characterized by a reductive shift of FAD, impairment of synaptic transmission and increasing interstitial potassium [K⁺]_o. Computer simulations predicted FAD changes to originate from the citric acid cycle enzyme α-ketoglutarate dehydrogenase and pyruvate dehydrogenase. In vivo, the FAD signal during early hypoxia displayed a reductive shift followed by a short oxidation associated with terminal spreading depolarization. In silico, initial tissue hypoxia followed by a transient re-oxygenation phase due to glucose depletion might explain FAD dynamics in vivo. Our work suggests that FAD fluorescence could be readily used to monitor mitochondrial function during hypoxia and represents a potential diagnostic tool to differentiate underlying metabolic processes for complementation of multimodal brain monitoring. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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16 pages, 3421 KiB

Open AccessArticle

Insights into the FMNAT Active Site of FAD Synthase: Aromaticity Is Essential for Flavin Binding and Catalysis

by Ana Serrano, Sonia Arilla-Luna and Milagros Medina

Int. J. Mol. Sci. 2020, 21(10), 3738; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103738 - 25 May 2020

Cited by 2 | Viewed by 2828

Abstract

The last step in the biosynthesis of flavin adenine dinucleotide (FAD) is considered a target for the design of antimicrobial drugs because it is carried out by two non-homologous proteins in eukaryotic and prokaryotic organisms. Monofunctional FMN: adenylyltransferases (FMNAT) in Eukarya and FMNAT modules of bifunctional FAD synthases (FADS) in Prokarya belong to different structural families with dissimilar chemistry and binding modes for the substrates. In this study, we analyzed the relevance of the hydrophobic environment of the flavin isoalloxazine in the FMNAT active site of Corynebacterium ammoniagenes FADS (CaFADS) through the mutational analysis of its F62, Y106, and F128 residues. They form the isoalloxazine binding cavity and are highly conserved in the prokaryotic FADS family. The spectroscopic, steady-state kinetics and thermodynamic data presented indicate that distortion of aromaticity at the FMNAT isoalloxazine binding cavity prevents FMN and FAD from correct accommodation in their binding cavity and, as a consequence, decreases the efficiency of the FMNAT activity. Therefore, the side-chains of F62, Y106 and F128 are relevant in the formation of the catalytic competent complex during FMNAT catalysis in CaFADS. The introduced mutations also modulate the activity occurring at the riboflavin kinase (RFK) module of CaFADS, further evidencing the formation of quaternary assemblies during catalysis. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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15 pages, 2153 KiB

Open AccessArticle

Reactions of Plasmodium falciparum Ferredoxin:NADP⁺ Oxidoreductase with Redox Cycling Xenobiotics: A Mechanistic Study

by Mindaugas Lesanavičius, Alessandro Aliverti, Jonas Šarlauskas and Narimantas Čėnas

Int. J. Mol. Sci. 2020, 21(9), 3234; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093234 - 02 May 2020

Cited by 12 | Viewed by 2387

Abstract

Ferredoxin:NADP⁺ oxidoreductase from Plasmodium falciparum (PfFNR) catalyzes the NADPH-dependent reduction of ferredoxin (PfFd), which provides redox equivalents for the biosynthesis of isoprenoids and fatty acids in the apicoplast. Like other flavin-dependent electrontransferases, PfFNR is a potential source of free radicals of quinones and other redox cycling compounds. We report here a kinetic study of the reduction of quinones, nitroaromatic compounds and aromatic N-oxides by PfFNR. We show that all these groups of compounds are reduced in a single-electron pathway, their reactivity increasing with the increase in their single-electron reduction midpoint potential (E¹₇). The reactivity of nitroaromatics is lower than that of quinones and aromatic N-oxides, which is in line with the differences in their electron self-exchange rate constants. Quinone reduction proceeds via a ping-pong mechanism. During the reoxidation of reduced FAD by quinones, the oxidation of FADH^. to FAD is the possible rate-limiting step. The calculated electron transfer distances in the reaction of PfFNR with various electron acceptors are similar to those of Anabaena FNR, thus demonstrating their similar “intrinsic” reactivity. Ferredoxin stimulated quinone- and nitro-reductase reactions of PfFNR, evidently providing an additional reduction pathway via reduced PfFd. Based on the available data, PfFNR and possibly PfFd may play a central role in the reductive activation of quinones, nitroaromatics and aromatic N-oxides in P. falciparum, contributing to their antiplasmodial action. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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17 pages, 4818 KiB

Open AccessArticle

Mutation of Aspartate 238 in FAD Synthase Isoform 6 Increases the Specific Activity by Weakening the FAD Binding

by Piero Leone, Michele Galluccio, Stefano Quarta, Ernesto Anoz-Carbonell, Milagros Medina, Cesare Indiveri and Maria Barile

Int. J. Mol. Sci. 2019, 20(24), 6203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246203 - 09 Dec 2019

Cited by 12 | Viewed by 3370

Abstract

FAD synthase (FADS, or FMN:ATP adenylyl transferase) coded by the FLAD1 gene is the last enzyme in the pathway of FAD synthesis. The mitochondrial isoform 1 and the cytosolic isoform 2 are characterized by the following two domains: the C-terminal PAPS domain (FADSy) performing FAD synthesis and pyrophosphorolysis; the N-terminal molybdopterin-binding domain (FADHy) performing a Co⁺⁺/K⁺-dependent FAD hydrolysis. Mutations in FLAD1 gene are responsible for riboflavin responsive and non-responsive multiple acyl-CoA dehydrogenases and combined respiratory chain deficiency. In patients harboring frameshift mutations, a shorter isoform (hFADS6) containing the sole FADSy domain is produced representing an emergency protein. With the aim to ameliorate its function we planned to obtain an engineered more efficient hFADS6. Thus, the D238A mutant, resembling the D181A FMNAT “supermutant” of C. glabrata, was overproduced and purified. Kinetic analysis of this enzyme highlighted a general increase of K_m, while the k_cat was two-fold higher than that of WT. The data suggest that the FAD synthesis rate can be increased. Additional modifications could be performed to further improve the synthesis of FAD. These results correlate with previous data produced in our laboratory, and point towards the following proposals (i) FAD release is the rate limiting step of the catalytic cycle and (ii) ATP and FMN binding sites are synergistically connected. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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14 pages, 2507 KiB

Open AccessArticle

Specific Features for the Competent Binding of Substrates at the FMN Adenylyltransferase Site of FAD Synthase from Corynebacterium ammoniagenes

by Sonia Arilla-Luna, Ana Serrano and Milagros Medina

Int. J. Mol. Sci. 2019, 20(20), 5083; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205083 - 14 Oct 2019

Cited by 5 | Viewed by 2409

Abstract

Bifunctional FAD synthases (FADSs) catalyze FMN (flavin mononucleotide) and FAD (flavinadenine dinucleotide) biosynthesis at their C-riboflavin kinase (RFK) and N-FMN:adenylyltransferase (FMNAT) modules, respectively. Biophysical properties and requirements for their FMNAT activity differ among species. Here, we evaluate the relevance of the integrity of the binding site of the isoalloxazine of flavinic substrates for FMNAT catalysis in Corynebacterium ammoniagenes FADS (CaFADS). We have substituted P56 and P58, belonging to a conserved motif, as well as L98. These residues shape the isoalloxazine FMNAT site, although they are not expected to directly contact it. All substitutions override enzyme ability to transform substrates at the FMNAT site, although most variants are able to bind them. Spectroscopic properties and thermodynamic parameters for the binding of ligands indicate that mutations alter their interaction modes. Substitutions also modulate binding and kinetic properties at the RFK site, evidencing the crosstalk of different protomers within CaFADS assemblies during catalysis. In conclusion, despite the FMNAT site for the binding of substrates in CaFADS appearing as a wide open cavity, it is finely tuned to provide the competent binding conformation of substrates. In particular, P56, P58 and L98 shape the isoalloxazine site to place the FMN- and FAD-reacting phosphates in optimal geometry for catalysis. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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12 pages, 2198 KiB

Open AccessArticle

Reconstitution in Proteoliposomes of the Recombinant Human Riboflavin Transporter 2 (SLC52A2) Overexpressed in E. coli

by Lara Console, Maria Tolomeo, Matilde Colella, Maria Barile and Cesare Indiveri

Int. J. Mol. Sci. 2019, 20(18), 4416; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184416 - 08 Sep 2019

Cited by 16 | Viewed by 3061

Abstract

Background: the SLC52A2 gene encodes for the riboflavin transporter 2 (RFVT2). This transporter is ubiquitously expressed. It mediates the transport of Riboflavin across cell membranes. Riboflavin plays a crucial role in cells since its biologically active forms, FMN and FAD, are essential for the metabolism of carbohydrates, amino acids, and lipids. Mutation of the Riboflavin transporters is a risk factor for anemia, cancer, cardiovascular disease, neurodegeneration. Inborn mutations of SLC52A2 are associated with Brown-Vialetto-van Laere syndrome, a rare neurological disorder characterized by infancy onset. In spite of the important metabolic and physio/pathological role of this transporter few data are available on its function and regulation. Methods: the human recombinant RFVT2 has been overexpressed in E. coli, purified and reconstituted into proteoliposomes in order to characterize its activity following the [³H]Riboflavin transport. Results: the recombinant hRFVT2 showed a Km of 0.26 ± 0.07 µM and was inhibited by lumiflavin, FMN and Mg²⁺. The Riboflavin uptake was also regulated by Ca²⁺. The native protein extracted from fibroblast and reconstituted in proteoliposomes also showed inhibition by FMN and lumiflavin. Conclusions: proteoliposomes represent a suitable model to assay the RFVT2 function. It will be useful for screening the mutation of RFVT2. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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Review

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32 pages, 2380 KiB

Open AccessReview

Development of Novel Experimental Models to Study Flavoproteome Alterations in Human Neuromuscular Diseases: The Effect of Rf Therapy

by Maria Tolomeo, Alessia Nisco, Piero Leone and Maria Barile

Int. J. Mol. Sci. 2020, 21(15), 5310; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155310 - 26 Jul 2020

Cited by 13 | Viewed by 6145

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. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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25 pages, 2975 KiB

Open AccessReview

Riboflavin Deficiency—Implications for General Human Health and Inborn Errors of Metabolism

by Signe Mosegaard, Graziana Dipace, Peter Bross, Jasper Carlsen, Niels Gregersen and Rikke Katrine Jentoft Olsen

Int. J. Mol. Sci. 2020, 21(11), 3847; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113847 - 28 May 2020

Cited by 88 | Viewed by 12822

Abstract

As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms. This review discusses the environmental, physiological and genetic factors that affect cellular riboflavin status. We describe the crucial role of riboflavin for general human health, and the clear benefits of riboflavin treatment in patients with inborn errors of metabolism. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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19 pages, 2625 KiB

Open AccessReview

Alteration of Electron Acceptor Preferences in the Oxidative Half-Reaction of Flavin-Dependent Oxidases and Dehydrogenases

by Kentaro Hiraka, Wakako Tsugawa and Koji Sode

Int. J. Mol. Sci. 2020, 21(11), 3797; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113797 - 27 May 2020

Cited by 12 | Viewed by 4534

Abstract

In this review, recent progress in the engineering of the oxidative half-reaction of flavin-dependent oxidases and dehydrogenases is discussed, considering their current and future applications in bioelectrochemical studies, such as for the development of biosensors and biofuel cells. There have been two approaches in the studies of oxidative half-reaction: engineering of the oxidative half-reaction with oxygen, and engineering of the preference for artificial electron acceptors. The challenges for engineering oxidative half-reactions with oxygen are further categorized into the following approaches: (1) mutation to the putative residues that compose the cavity where oxygen may be located, (2) investigation of the vicinities where the reaction with oxygen may take place, and (3) investigation of possible oxygen access routes to the isoalloxazine ring. Among these approaches, introducing a mutation at the oxygen access route to the isoalloxazine ring represents the most versatile and effective strategy. Studies to engineer the preference of artificial electron acceptors are categorized into three different approaches: (1) engineering of the charge at the residues around the substrate entrance, (2) engineering of a cavity in the vicinity of flavin, and (3) decreasing the glycosylation degree of enzymes. Among these approaches, altering the charge in the vicinity where the electron acceptor may be accessed will be most relevant. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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22 pages, 4535 KiB

Open AccessReview

Riboflavin: The Health Benefits of a Forgotten Natural Vitamin

by Nittiya Suwannasom, Ijad Kao, Axel Pruß, Radostina Georgieva and Hans Bäumler

Int. J. Mol. Sci. 2020, 21(3), 950; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030950 - 31 Jan 2020

Cited by 174 | Viewed by 19247

Abstract

Riboflavin (RF) is a water-soluble member of the B-vitamin family. Sufficient dietary and supplemental RF intake appears to have a protective effect on various medical conditions such as sepsis, ischemia etc., while it also contributes to the reduction in the risk of some forms of cancer in humans. These biological effects of RF have been widely studied for their anti-oxidant, anti-aging, anti-inflammatory, anti-nociceptive and anti-cancer properties. Moreover, the combination of RF and other compounds or drugs can have a wide variety of effects and protective properties, and diminish the toxic effect of drugs in several treatments. Research has been done in order to review the latest findings about the link between RF and different clinical aberrations. Since further studies have been published in this field, it is appropriate to consider a re-evaluation of the importance of RF in terms of its beneficial properties. Full article

(This article belongs to the Special Issue Flavin Adenine Dinucleotide (FAD): Biosynthesis and Function)

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