Fig 1
Overview of NAD biosynthesis in humans. NAD biosynthesis initiates from different entry points. Nicotinamide phosphoribosyltransferase (NamPRT) and nicotinic acid phosphoribosyltransferase (NAPRT) catalyze the respective conversion of nicotinamide (Nam) and nicotinic acid (NA) to the intermediates nicotinamide mononucleotide (NMN) and nicotinic acid mononucleotide (NAMN). Transformation of quinolinic acid (QA) by quinolinic acid phosphoribosyltransferase (QAPRT) also yields NAMN. All three reactions use phosphoribosyl pyrophosphate (PRPP) as phosphoribosyl donor. Nicotinamide riboside kinase (NRK) activity transforms nicotinamide riboside (NR) or nicotinic acid riboside (NAR) to NMN and NAMN, respectively. Dinucleotide formation, the single common step in all routes, is catalyzed by nicotinamide adenylyltransferase (NMNAT) yielding nicotinic acid adenine dinucleotide (NAAD) from NAMN or nicotinamide adenine dinucleotide (NAD) from NMN. Finally, NAD synthetase (NADS) converts NAAD to NAD in an amidation reaction using glutamine as substrate. The amide group of nicotinamide related structures is highlighted in blue, the carboxyl group of nicotinic acid related structures is highlighted in red.
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NAD plays a major role in all cells as substrate for signal transduction and as cofactor in metabolic redox reactions. Since NAD-dependent signaling involves degradation of the nucleotide, continuous restoration of cellular NAD pools is essential. Moreover, NAD-dependent signaling reactions, which include ADP-ribosylation, protein deacetylation by...
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NAD⁺ is a vital redox cofactor and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Supplementation with NAD⁺ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), protects against metabolic disease, neurodegenerative disorders and age-related physiolog...
Nicotinamide adenine dinucleotide (NAD) and its phosphorylated form NADP are the major coenzymes in the redox reactions of various essential metabolic pathways. NAD⁺ also serves as a substrate for several families of regulatory proteins, such as protein deacetylases (sirtuins), ADP-ribosyltransferases, and poly(ADP-ribose) polymerases, that control...
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... Although it exists in α and β anomeric forms, only the β form is the active anomer, which is also termed β-nicotinamide mononucleotide, β-nicotinamide D-ribonucleotide, and β-nicotinamide ribose monophosphate. Inside the cell, NMN is converted into nicotinamide adenine dinucleotide (NAD + ), which is an essential molecule in cells where it functions as an electron carrier in metabolic redox reactions and as a substrate for NAD-dependent signal transduction [1]. Deficiency of NAD + can be compensated for with NMN supplementation, which effectively increases NAD + levels in various tissues and prevents related metabolic diseases [2]. ...
... When NAM is used as a precursor, NMN is formed by NAMPT. NAMPT is found in mammals and some pathogenic microorganisms, and studies on its regulation have focused on mammalian cells such as humans and mice [1,27]. The catalytic activity of human NAMPT could be increased from 1.60 ± 0.06 × 10 3 to 1.8 ± 0.9 × 10 6 M −1 ·s −1 by hydrolytic coupling with ATP [28]. ...
Nicotinamide mononucleotide (NMN) is an essential precursor of nicotinamide adenine dinucleotide (NAD+), which is widely applied in the pharmaceutical and biotech industries. The biosynthesis of NMN is currently attracting much attention because it has non-toxic reaction conditions and low amounts of isomers, whereas chemical synthesis has low yields and is not environmentally friendly. This review systematically describes the two biosynthetic pathways of NMN in detail for the first time and introduces the latest studies on NMN production through different pathways using metabolic engineering strategies. NMN accumulation can be improved by optimizing the activity of key enzymes, enhancing the supply of precursors and co-factors, inhibiting the synthesis of byproducts, and promoting product export. Finally, we also discuss the current challenges of producing NMN and possible solutions for the future.
... NAD and precursors within NAD biosynthetic pathways are implicated in many human illnesses as well as the normal aging process [2]. Molecular modulation of the activity of NAD synthesizing enzymes is also under investigation [7,8]. The first highly specific and potent inhibitor of NAMPT, designated FK866 or APO866, was identified in 2003 [9]. ...
Nicotinamide adenine dinucleotide (NAD) is a central molecule in cellular metabolism that has been implicated in human health, the aging process, and an array of human diseases. NAD is well known as an electron storage molecule, cycling between NAD and the reduced NADH. In addition, NAD is cleaved into nicotinamide and Adenine diphosphate ribose by NAD-consuming enzymes such as sirtuins, PARPs and CD38. There are numerous pathways for the biosynthesis of NAD to maintain a baseline concentration and thus avoid cellular death. The NAD salvage pathway, a two-step process to regenerate NAD after cleavage, is the predominant pathway for humans. Nicotinamide PhosphribosylTransferase (NAMPT) is the rate-limiting enzyme within the salvage path. Exposure to pharmacological modulators of NAMPT has been reported to either deplete or increase NAD levels. This study used a curated set of virtual compounds coupled with biochemical assays to identify novel activators of NAMPT. Autodock Vina generated a ranking of the National Cancer Institute's Diversity Set III molecular library. The library contains a set of organic molecules with diverse functional groups and carbon skeletons that can be used to identify lead compounds. The target NAMPT surface encompassed a novel binding location that included the NAMPT dimerization plane, the openings to the two active site channels, and a portion of the known binding location for NAMPT substrate and product. Ranked molecules were evaluated in a biochemical assay using purified recombinant NAMPT enzyme. Two novel carbon skeletons were confirmed to stimulate NAMPT activity. Compound 20 (NSC9037) is a polyphenolic xanthene derivative in the fluorescein family, while compound 2 (NSC19803) is the polyphenolic myricitrin nature product. Micromolar quantities of compound 20 or compound 2 can double NAMPT's product formation. In addition, natural products that contain high concentrations of polyphenolic flavonoids, similar to myricitrin, also stimulate NAMPT activity. Confirmation of a novel binding site for these compounds will further our understanding of the cellular mechanism leading to NAD homeostasis and better human health outcomes.
... The long-known universal coenzyme nicotinamide adenine dinucleotide (NAD) plays an important role in energetic metabolism both as a cofactor in redox reactions and as a substrate for NAD-consuming enzymes that regulate critical cellular processes (e.g., inflammatory response, metabolic adaptation, differentiation, and signal transduction) [1][2][3]. Since NAD is cleaved by the catalytic activity of NAD-consuming enzymes, it needs to be continuously replenished. Its biosynthesis is ensured by multiple biosynthetic pathways that start from different precursors, including tryptophan and the three forms of vitamin B3, i.e., nicotinic acid (NA), nicotinamide (NAM), and nicotinamide riboside (NR). ...
... The reaction mixture was stirred overnight at r.t., washed with brine, dried over Na2SO4, and concentrated to get the crude product, which was purified by flash chromatography eluting with CHCl3/MeOH (95:5) to yield an oil (55% yield). The free base was transformed into the hydrochloride salt, which was recrystallized from 2-PrOH to obtain a red solid (m.p. 148-150° C). 1 (18) This compound was prepared starting from 36 and 38 following the procedure described for 17: an oil was obtained (49% yield). The free base was transformed into the hydrochloride salt, which was recrystallized from 2-PrOH, to obtain a white solid (m.p. 198-200 °C). 1 (19) Compound 39 (1.0 mmol) was treated with 2.5N HCl in MeOH (10 mL) and the mixture was stirred at r.t. for 1h. ...
... The free base was transformed into the hydrochloride salt, which was recrystallized from 2-PrOH, to obtain a white solid (m.p. 198-200 °C). 1 (19) Compound 39 (1.0 mmol) was treated with 2.5N HCl in MeOH (10 mL) and the mixture was stirred at r.t. for 1h. Evaporation of the solvent gave the crude product, which was recrystallized from 2-PrOH, to obtain a red solid (m.p. 250-253 °C). 1 Compound 45 (6.72 mmol) was hydrogenated at 40 psi in MeOH for 2 h at r.t. ...
The prevention of nicotinamide adenine dinucleotide (NAD) biosynthesis is considered an attractive therapeutic approach against cancer, considering that tumor cells are characterized by an increased need for NAD to fuel their reprogrammed metabolism. On the other hand, the decline of NAD is a hallmark of some pathological conditions, including neurodegeneration and metabolic diseases, and boosting NAD biosynthesis has proven to be of therapeutic relevance. Therefore, targeting the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT), which regulate NAD biosynthesis from nicotinamide (NAM) and nicotinic acid (NA), respectively, is considered a promising strategy to modulate intracellular NAD pool. While potent NAMPT inhibitors and activators have been developed, the search for NAPRT modulators is still in its infancy. In this work, we report on the identification of a new class of NAPRT modulators bearing the 1,2-dimethylbenzimidazole scaffold properly substituted in position 5. In particular, compounds 24, 31, and 32 emerged as the first NAPRT activators reported so far, while 18 behaved as a noncompetitive inhibitor toward NA (Ki = 338 µM) and a mixed inhibitor toward phosphoribosyl pyrophosphate (PRPP) (Ki = 134 µM). From in vitro pharmacokinetic studies, compound 18 showed an overall good ADME profile. To rationalize the obtained results, docking studies were performed on the NAPRT structure. Moreover, a preliminary pharmacophore model was built to shed light on the shift from inhibitors to activators.
... All three enzymes are required for NAD synthesis. NAD, referring to the redox couple NAD + and NADH, is derived from dietary tryptophan through the NAD de novo synthesis pathway (also termed the kynurenine pathway), or from vitamin B3 via the Preiss-Handler and Salvage pathways (Dolle et al., 2013;Griffiths et al., 2020;Houtkooper et al., 2010). Vitamin B3 is a collective term for the NAD precursors nicotinic acid, nicotinamide and nicotinamide riboside. ...
... The NAD de novo synthesis pathway is the major pathway in mammals, accounting for ∼90% of tryptophan catabolism. Thus, dietary supply of tryptophan is linked to NAD synthesis (Dolle et al., 2013;Sainio et al., 1996). Hartnup disorder, an autosomal-recessive disorder caused by mutations in SLC6A19, affects one in 30,000 individuals and is characterised by a severely elevated urinary neutral amino acid excretion (aminoaciduria) (Kleta et al., 2004;Scriver, 1965;Seow et al., 2004). ...
Nicotinamide adenine dinucleotide (NAD) is a key metabolite synthesised from vitamin B3 or tryptophan. Disruption of genes encoding NAD synthesis enzymes reduces NAD levels and causes congenital NAD deficiency disorder (CNDD), characterised by multiple congenital malformations. SLC6A19 (encoding B0AT1, a neutral amino acid transporter), represents the main transporter for free tryptophan in the intestine and kidney. Here, we tested whether Slc6a19 heterozygosity in mice limits the tryptophan available for NAD synthesis during pregnancy and causes adverse pregnancy outcomes. Pregnant Slc6a19+/− mice were fed diets depleted of vitamin B3, so that tryptophan was the source of NAD during gestation. This perturbed the NAD metabolome in pregnant Slc6a19+/− females, resulting in reduced NAD levels and increased rates of embryo loss. Surviving embryos were small and exhibited specific combinations of CNDD-associated malformations. Our results show that genes not directly involved in NAD synthesis can affect NAD metabolism and cause CNDD. They also suggest that human female carriers of a SLC6A19 loss-of-function allele might be susceptible to adverse pregnancy outcomes unless sufficient NAD precursor amounts are available during gestation.
This article has an associated First Person interview with the first author of the paper.
... Des altérations des gènes suppresseurs de tumeurs peuvent également aboutir à une dérégulation du métabolisme nucléotidique des cancers. Des mutations du gène TP53 aboutissaient par exemple à la synthèse d'une protéine modifiée capable de se fixer au niveau du promoteur de nombreux gènes activateurs de la synthèse des nucléotides et d'augmenter leur expression [283]. La Liver Kinase B1 (LKB1) ou serine thréonine kinase 11 (STK11) active la protéine kinase activée par l'AMP (AMPK), une enzyme clé de la régulation énergétique. ...
Contexte : La radiothérapie (RT) est couramment utilisée pour la prise en charge des tumeurs digestives, notamment le cancer du rectum (RC) et l'adénocarcinome du canal pancréatique (PDAC). La RT est souvent associée à la chimiothérapie pour en augmenter l'efficacité, au prix d'une toxicité importante. La radiochimiothérapie ne peut donc être proposée à tous les patients. Les composants bioactifs (BFC) d'origine naturelle, dont le resvératrol et la capsaïcine, peuvent potentialiser l'effet antitumoral des rayonnements ionisants. Cette radiosensibilisation peut être d'un grand intérêt si les tissus sains environnants sont épargnés. Objectifs : Ce travail a évalué la radiosensibilisation de modèles de PDAC et de RC par le resvératrol et la capsaïcine et a exploré les mécanismes impliqués dans leur action spécifique aux tumeurs, aux niveaux cellulaire et moléculaire. Méthodes : La survie cellulaire a été évaluée in vitro en présence de BFC sur différentes lignées cellulaires tumorales et non tumorales de PDAC et CRC. La métabolisation du resvératrol a été évaluée par spectrométrie de masse et corrélée avec l'expression des gènes des UDP-glucosyltransferases 1A (UGT1A ) par RT-qPCR. L'implication des enzymes UGT1A dans la sensibilité au resvératrol des cellules colorectales a été établie par modulation de l'expression des UGT1A. L’effet radiosensibilisant des BFCs a été évalué via l’exploration des processus d’apoptose et de leur impact sur le cycle cellulaire. Les voies moléculaires impliquées dans la radiosensibilisation ont été analysées par western blot. L'analyse de radiosensibilisation in vivo a été testée sur des xénogreffes de cellules tumorales humaines sous- cutanées. Résultats : Le resvératrol (R) et la capsaïcine (C) présentaient un effet cytotoxique sur les cellules tumorales et cet effet était renforcé par leur combinaison. Parallèlement, le cycle cellulaire était arrêté et l'apoptose induite. La résistance au resvératrol était liée à l'expression des gènes UGT1A dans les lignées digestives tumorales et non tumorales. L’inhibition de l'expression du gène UGT1A10 par shRNA permettait de réduire la métabolisation du resvératrol et augmentait sa toxicité. À l'inverse, lasurexpression du gène UGT1A10 augmentait la métabolisation et s’accompagnait d'une diminution de la cytotoxicité. Le resvératrol affectait l'homéostasie des cellules tumorales intestinales avec notamment une diminution des niveaux de nucléotides pyrimidiques, aboutissant à une réduction globale de la transcription et de la traduction. Cet effet n’était pas observé sur les cellules non-tumorales. Le resvératrol et la capsaïcine radiosensibilisaient les tumeurs xénogreffées en induisant un arrêt du cycle cellulaire et à une augmentation de l'apoptose. De plus, un meilleur contrôle de la croissance tumorale était obtenu pour les souris irradiées et traitées par les BFCs par rapport aux souris recevant uniquement la RT. Enfin, le traitement par BFCs engendrait un déséquilibre de la voie de réparation de l'ADN radio-induite amplifiant le phénomène apoptotique dans le modèle murin de tumeur PDAC. Conclusions : Les BFCs représentent des agents radiosensibilisants des tumeurs digestives prometteurs. Le resvératrol présente une cytotoxicité spécifique aux tumeurs lié fonctionnellement avec l'expression des gènes UGT1A dans les cellules et les tissus tumoraux digestifs. De plus, les BFCs et en particulier le resvératrol affectent l'homéostasie globale des cellules tumorales, en altérant les fonctions cellulaires de base. La combinaison du resvératrol et de la capsaïcine radiosensibilise les tumeurs pancréatiques et colorectales dans des modèles précliniques murins. Ces travaux positionnent les BFCs comme des solutions alternatives pour la radiosensibilisation des tumeurs, sans effet secondaire systémique souvent observé avec la chimiothérapie conventionnelle.
... Niacinamide is a form of vitamin B3, which, along with tryptophan, serves as a source of nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+), and their reduced forms (Makarov et al., 2019). Studies show that NAD+ is an important cofactor in metabolic redox reactions, and that it is involved in the regulation of cell death processes (Dölle et al., 2013). A clinical trial (registered as NCT00605930) on the safety and tolerance of a 6-month treatment with creatine, pyruvate, and niacinamide assessed their ability to penetrate the BBB, as measured by their metabolite concentrations in the cerebrospinal fluid (CSF). ...
Background: Atypical parkinsonian syndromes are rare, fatal neurodegenerative diseases associated with abnormal protein accumulation in the brain. Examples of these syndromes include progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration. A common clinical feature in parkinsonism is a limited improvement with levodopa. So far, there are no disease-modifying treatments to address these conditions, and therapy is only limited to the alleviation of symptoms. Diagnosis is devastating for patients, as prognosis is extremely poor, and the disease tends to progress rapidly. Currently, potential causes and neuropathological mechanisms involved in these diseases are being widely investigated.
Objectives: The goal of this review is to summarize recent advances and gather emerging disease-modifying therapies that could slow the progression of atypical parkinsonian syndromes.
Methods: PubMed and Google Scholar databases were searched regarding novel perspectives for atypical parkinsonism treatment. The following medical subject headings were used: “atypical parkinsonian syndromes—therapy,” “treatment of atypical parkinsonian syndromes,” “atypical parkinsonian syndromes—clinical trial,” “therapy of tauopathy,” “alpha-synucleinopathy treatment,” “PSP therapy/treatment,” “CBD therapy/treatment,” “MSA therapy/treatment,” and “atypical parkinsonian syndromes—disease modifying.” All search results were manually reviewed prior to inclusion in this review.
Results: Neuroinflammation, mitochondrial dysfunction, microglia activation, proteasomal impairment, and oxidative stress play a role in the neurodegenerative process. Ongoing studies and clinical trials target these components in order to suppress toxic protein accumulation. Various approaches such as stem cell therapy, anti-aggregation/anti-phosphorylation agent administration, or usage of active and passive immunization appear to have promising results.
Conclusion: Presently, disease-modifying strategies for atypical parkinsonian syndromes are being actively explored, with encouraging preliminary results. This leads to an assumption that developing accurate, safe, and progression-halting treatment is not far off. Nevertheless, the further investigation remains necessary.
... El conocer los mecanismos mediante los cuales los seres vivos obtienen NAD es particularmente importante para comprender la relación entre su metabolismo y las alteraciones que conducen a enfermedades (Berger, et al., 2004). Las perturbaciones en la regulación de la síntesis del NAD derivan en deficiencias fatales para el organismo (Dolle, et al., 2013;Mao, et al., 2016;Padiadpu, et al., 2016;Sauve, 2008). Además, las particularidades de las rutas bioquímicas que involucran el NAD en organismos patógenos pueden considerarse como posibles blancos terapéuticos contra enfermedades infecciosas. ...
La nicotinamida/nicotinato mononucleótido adenililtransferasa (NMNAT, EC 2.7.7.1/18) desempeñauna función central en la síntesis del dinucleótido de adenina y nicotinamida (NAD) debido a queen esta enzima confluyen las rutas de síntesis de novo y de reciclaje. El NAD es una moléculatrascendental en el metabolismo de todos los seres vivos, principalmente en el metabolismo redox. Eneste estudio se presenta una nueva estrategia metodológica para la evaluación de posibles inhibidoresde la NMNAT de Leishmania braziliensis (LbNMNAT). El método suprime la actividad inhibitoriacruzada con la enzima acoplada al ensayo de detección, la alcohol dehidrogenasa (ADH, EC 1.1.1.1).Experimentalmente se introdujo un paso intermedio de extracción en fase sólida de los inhibidoresantes de la ejecución del sistema enzimático de detección. La implementación del paso de extracciónposibilitó la evaluación específica de la enzima de interés, la LbNMNAT, sin afectar la enzimaacoplada ADH. El nuevo método permitió estudiar el efecto inhibitorio de la galotanina, productonatural de especies del género Rhus (Rhus chinensis), en la actividad de la LbNMNAT.
... Nucleotides and their derivatives play many key roles in the cell: beyond the genetic material making up DNA (nucleotides) and RNA (ribonucleotides). Nucleotides can be the base in other molecules such as the energy molecule ATP, coenzymes like NAD or NADP, or signalling molecules such as cAMP [72,73]. Nucleotide biosynthesis plays a key role in regulating cell growth and cell transformation [74,75]. ...
The ductus arteriosus (DA) connects the fetal pulmonary artery and aorta, diverting placentally oxygenated blood from the developing lungs to the systemic circulation. The DA constricts in response to increases in oxygen (O2) with the first breaths, resulting in functional DA closure, with anatomic closure occurring within the first days of life. Failure of DA closure results in persistent patent ductus arteriosus (PDA), a common complication of extreme preterm birth. The DA's response to O2, though modulated by the endothelium, is intrinsic to the DA smooth muscle cells (DASMC). DA constriction is mediated by mitochondrial-derived reactive oxygen species, which increase in proportion to arterial partial pressure of oxygen (PaO2). The resulting redox changes inhibit voltage-gated potassium channels (Kv) leading to cell depolarization, calcium influx and DASMC constriction. To date, there has not been an unbiased assessment of the human DA O2-sensors using transcriptomics, nor are there known molecular mechanisms which characterize DA closure. DASMCs were isolated from DAs obtained from 10 term infants at the time of congenital heart surgery. Cells were purified by flow cytometry, negatively sorting using CD90 and CD31 to eliminate fibroblasts or endothelial cells, respectively. The purity of the DASMC population was confirmed by positive staining for α-smooth muscle actin, smoothelin B and caldesmon staining. Cells were grown for 96 h in hypoxia (2.5% O2) or normoxia (19% O2) and confocal imaging with Cal-520 was used to determine oxygen responsiveness. An oxygen-induced increase in intracellular calcium of 18.1% ± 4.4% and SMC constriction (−27% ± 1.5% shortening) occurred in all cell lines within five minutes. RNA sequencing of the cells grown in hypoxia and normoxia revealed significant regulation of 1344 genes (corrected p < 0.05). We examined these genes using Gene Ontology (GO). This unbiased assessment of altered gene expression indicated significant enrichment of the following GOterms: mitochondria, cellular respiration and transcription. The top regulated biologic process was generation of precursor metabolites and energy. The top regulated cellular component was mitochondrial matrix. The top regulated molecular function domain was transcription coactivator activity. Multiple members of the NADH-ubiquinone oxidoreductase (NDUF) family are upregulated in human DASMC (hDASMC) following normoxia. Several of our differentially regulated transcripts are encoded by genes that have been associated with genetic syndromes that have an increased incidence of PDA (Crebb binding protein and Histone Acetyltransferase P300). This first examination of the effects of O2 on human DA transcriptomics supports a putative role for mitochondria as oxygen sensors.
... In addition to the NAMPT-dependent NAD + synthesizing pathway, alternative precursors can also maintain cellular NAD + homeostasis. Quinolinic acid, a product of tryptophan degradation in the kynurenine pathway, is converted to NAMN, the acidic form of NMN, and thereby enters NAD + synthesis [21]. This route appears to be important for liver NAD + homeostasis, at least in mice [22]. ...
... This route appears to be important for liver NAD + homeostasis, at least in mice [22]. Likewise, nicotinic acid is also converted to NAMN by nicotinic acid phosphoribosyltransferase. NMNATs form the dinucleotide, NAAD, from NAMN and ATP, in the same manner as NAD + from NMN and ATP [21]. Thus, all NAD + biosynthetic pathways require NMNAT activity [23]. ...
... Thus, all NAD + biosynthetic pathways require NMNAT activity [23]. In mammals, NAAD is amidated to NAD + by NAD + synthetase using glutamine as an amide donor and the energy of ATP to accomplish the reaction [21]. Thereby, the conversion of Nam to NAD + through NAMPT activity is not only the shortest, but also the energetically least-demanding pathway. ...
Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD+ had long remained obscure. Only just recently, the existence of a human mitochondrial NAD+ carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD+ carrier in mammals, a long-standing mystery in NAD+ biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery.
... The main mechanism for the mainte nance of NAD level in human cells is its synthesis from Nam, which is supplied with a diet and formed as a result of NAD + cleavage in various regulatory processes. NAD can be also synthesized from other forms of vitamin B3 and produced de novo from tryptophan [35,37,38]. ...
Proteins of the NUDIX hydrolase (NUDT) superfamily that cleave organic pyrophosphates are found in all classes of organisms, from archaea and bacteria to higher eukaryotes. In mammals, NUDTs exhibit a wide range of functions and are characterized by different substrate specificity and intracellular localization. They control the concentration of various metabolites in the cell, including key regulatory molecules such as nicotinamide adenine dinucleotide (NAD), ADP-ribose, and their derivatives. In this review, we discuss the role of NUDT proteins in the metabolism of NAD and ADP-ribose in human and animal cells.
