scholarly journals Microbial NAD Metabolism: Lessons from Comparative Genomics

2009 ◽  
Vol 73 (3) ◽  
pp. 529-541 ◽  
Author(s):  
Francesca Gazzaniga ◽  
Rebecca Stebbins ◽  
Sheila Z. Chang ◽  
Mark A. McPeek ◽  
Charles Brenner
Keyword(s):  
Nicotinic Acid ◽  
De Novo ◽  
Strictly Aerobic ◽  
Bacterial Dna ◽  
Nad Metabolism ◽  
Dna Ligases ◽  
Nicotinamide Riboside ◽  
Nad Synthesis ◽  
Biochemical Genetic ◽  
Lysine Deacetylases

SUMMARY NAD is a coenzyme for redox reactions and a substrate of NAD-consuming enzymes, including ADP-ribose transferases, Sir2-related protein lysine deacetylases, and bacterial DNA ligases. Microorganisms that synthesize NAD from as few as one to as many as five of the six identified biosynthetic precursors have been identified. De novo NAD synthesis from aspartate or tryptophan is neither universal nor strictly aerobic. Salvage NAD synthesis from nicotinamide, nicotinic acid, nicotinamide riboside, and nicotinic acid riboside occurs via modules of different genes. Nicotinamide salvage genes nadV and pncA, found in distinct bacteria, appear to have spread throughout the tree of life via horizontal gene transfer. Biochemical, genetic, and genomic analyses have advanced to the point at which the precursors and pathways utilized by a microorganism can be predicted. Challenges remain in dissecting regulation of pathways.

scholarly journals NAD precursors cycle between host tissues and the gut microbiome

2021 ◽  
Author(s):  
Karthikeyani Chellappa ◽  
Melanie R McReynolds ◽  
Wenyun Lu ◽  
Xianfeng Zeng ◽  
Mikhail Makarov ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Nicotinic Acid ◽  
Gut Microbiome ◽  
Nicotinamide Adenine Dinucleotide ◽  
Proximal Part ◽  
Main Route ◽  
Nicotinamide Riboside ◽  
Dietary Consumption ◽  
Nad Synthesis ◽  
Host Tissues

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in both mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome. We find that preferred dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports gut microbiome NAD synthesis. In addition, the microbiome converts nicotinamide, originating from the host circulation, into nicotinic acid. Host tissues uptake and utilize this microbiome-derived nicotinic acid for NAD synthesis, maintaining circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, NAD precursors cycle between the host and gut microbiome to maintain NAD homeostasis.

scholarly journals Pathway analysis of NAD+ metabolism

2011 ◽  
Vol 439 (2) ◽  
pp. 341-348 ◽  
Author(s):  
Luis F. de Figueiredo ◽  
Toni I. Gossmann ◽  
Mathias Ziegler ◽  
Stefan Schuster
Keyword(s):  
Dna Repair ◽  
De Novo ◽  
Redox Balance ◽  
Transfer Reactions ◽  
Biosynthetic Pathways ◽  
De Novo Synthesis ◽  
Systematic Analysis ◽  
Nad Metabolism ◽  
Nad Synthesis ◽  
Futile Cycles

NAD+ is well known as a crucial cofactor in the redox balance of metabolism. Moreover, NAD+ is degraded in ADP-ribosyl transfer reactions, which are important components of multitudinous signalling reactions. These include reactions linked to DNA repair and aging. In the present study, using the concept of EFMs (elementary flux modes), we established all of the potential routes in a network describing NAD+ biosynthesis and degradation. All known biosynthetic pathways, which include de novo synthesis starting from tryptophan as well as the classical Preiss–Handler pathway and NAD+ synthesis from other vitamin precursors, were detected as EFMs. Moreover, several EFMs were found that degrade NAD+, represent futile cycles or have other functionalities. The systematic analysis and comparison of the networks specific for yeast and humans document significant differences between species with regard to the use of precursors, biosynthetic routes and NAD+-dependent signalling.

Nicotinamide adenine dinucleotide metabolism in plants. I. Intermediates of biosynthesis in wheat leaves and the effect of benzimidazole

1970 ◽  
Vol 48 (12) ◽  
pp. 2267-2278 ◽  
Author(s):  
H. R. Godavari ◽  
E. R. Waygood
Keyword(s):  
Nicotinic Acid ◽  
Nicotinamide Adenine Dinucleotide ◽  
Triticum Aestivum L ◽  
Total Radioactivity ◽  
Significant Loss ◽  
Nicotinamide Adenine ◽  
Nad Metabolism ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Wheat Leaves

Leaves of wheat (Triticum aestivum L. var. Selkirk) were incubated with nicotinic acid-7-14C and nicotinamide-7-14C for varying time periods from 5 min to 12 h. Aliquots of alcoholic extracts of leaves were subjected to paper chromatography and radioautography to isolate the intermediates of the synthesis and breakdown of nicotinamide adenine dinucleotide. Nine compounds were isolated quantitatively and identified as intermediates in the pathway of NAD metabolism. All the intermediates were labeled rapidly and the rapidity of labeling became a problem in rigorously proving the sequential operation of the pathway. The results indicate that the Preiss-Handler pathway: nicotinic acid→nicotinic acid mononucleotide→nicotinic acid adenine dinucleotide→NAD operates in wheat leaves. The degradation of NAD proceeded from NAD→nicotinamide mononucleotide→nicotinamide riboside→nicotinamide. Deamidation of the nicotinamide to nicotinic acid initiated a fresh cycle of biosynthesis. The total radioactivity recovered in the intermediates indicates that no measurable amount was lost to other metabolic pathways. Nicotinamide is recovered without significant loss and recycled. The rapid appearance of labeled nicotinamide indicates a possible interconversion of nicotinic acid and nicotinamide. About 80% of the radioactivity accumulated was present in trigonelline which is considered, on the basis of other evidence, to be a non-toxic form of nicotinic acid. Benzimidazole treatment of the leaves increased the incorporation of 14C into NADP.

scholarly journals Telomeric and rDNA Silencing in Saccharomyces cerevisiae Are Dependent on a Nuclear NAD+ Salvage Pathway

Genetics ◽  
2002 ◽  
Vol 160 (3) ◽  
pp. 877-889
Author(s):  
Joseph J Sandmeier ◽  
Ivana Celic ◽  
Jef D Boeke ◽  
Jeffrey S Smith
Keyword(s):  
Nicotinic Acid ◽  
Immunofluorescence Microscopy ◽  
De Novo ◽  
Histidine Residue ◽  
Salvage Pathway ◽  
Pathway Gene ◽  
Nad Synthesis ◽  
Dependent Protein ◽  
Protein Deacetylase ◽  
Growing Population

Abstract The Sir2 protein is an NAD+-dependent protein deacetylase that is required for silencing at the silent mating-type loci, telomeres, and the ribosomal DNA (rDNA). Mutations in the NAD+ salvage gene NPT1 weaken all three forms of silencing and also cause a reduction in the intracellular NAD+ level. We now show that mutation of a highly conserved histidine residue in Npt1p results in a silencing defect, indicating that Npt1p enzymatic activity is required for silencing. Deletion of another NAD+ salvage pathway gene called PNC1 caused a less severe silencing defect and did not significantly reduce the intracellular NAD+ concentration. However, silencing in the absence of PNC1 was completely dependent on the import of nicotinic acid from the growth medium. Deletion of a gene in the de novo NAD+ synthesis pathway BNA1 resulted in a significant rDNA silencing defect only on medium deficient in nicotinic acid, an NAD+ precursor. By immunofluorescence microscopy, Myc-tagged Bna1p was localized throughout the whole cell in an asynchronously growing population. In contrast, Myc-tagged Npt1p was highly concentrated in the nucleus in ~40% of the cells, indicating that NAD+ salvage occurs in the nucleus in a significant fraction of cells. We propose a model in which two components of the NAD+ salvage pathway, Pnc1p and Npt1p, function together in recycling the nuclear nicotinamide generated by Sir2p deacetylase activity back into NAD+.

scholarly journals Dual control of NAD+ synthesis by purine metabolites in yeast

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Benoît Pinson ◽  
Johanna Ceschin ◽  
Christelle Saint-Marc ◽  
Bertrand Daignan-Fornier
Keyword(s):  
Transcription Factors ◽  
Nicotinic Acid ◽  
Biomass Production ◽  
De Novo ◽  
Regulatory Role ◽  
Dual Control ◽  
Integrated Process ◽  
Nad Synthesis ◽  
Intermediate Metabolites ◽  
Pyridine Metabolism

Metabolism is a highly integrated process resulting in energy and biomass production. While individual metabolic routes are well characterized, the mechanisms ensuring crosstalk between pathways are poorly described, although they are crucial for homeostasis. Here, we establish a co-regulation of purine and pyridine metabolism in response to external adenine through two separable mechanisms. First, adenine depletion promotes transcriptional upregulation of the de novo NAD+ biosynthesis genes by a mechanism requiring the key-purine intermediates ZMP/SZMP and the Bas1/Pho2 transcription factors. Second, adenine supplementation favors the pyridine salvage route resulting in an ATP-dependent increase of intracellular NAD+. This control operates at the level of the nicotinic acid mononucleotide adenylyl-transferase Nma1 and can be bypassed by overexpressing this enzyme. Therefore, in yeast, pyridine metabolism is under the dual control of ZMP/SZMP and ATP, revealing a much wider regulatory role for these intermediate metabolites in an integrated biosynthesis network.

scholarly journals Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1615
Author(s):  
Jiachen Lin ◽  
Lina Zhao ◽  
Sen Zhao ◽  
Shengjie Li ◽  
Zhengye Zhao ◽  
...  
Keyword(s):  
De Novo ◽  
Multiple Organ ◽  
Vitro Assay ◽  
Nad Metabolism ◽  
Protein Levels ◽  
Functional Variants ◽  
Nad Synthesis ◽  
Genetic Perturbations ◽  
Biallelic Mutations

Genetic perturbations in nicotinamide adenine dinucleotide de novo (NAD) synthesis pathway predispose individuals to congenital birth defects. The NADSYN1 encodes the final enzyme in the de novo NAD synthesis pathway and, therefore, plays an important role in NAD metabolism and organ embryogenesis. Biallelic mutations in the NADSYN1 gene have been reported to be causative of congenital organ defects known as VCRL syndrome (Vertebral-Cardiac-Renal-Limb syndrome). Here, we analyzed the genetic variants in NADSYN1 in an exome-sequenced cohort consisting of patients with congenital vertebral malformations (CVMs). A total number of eight variants in NADSYN1, including two truncating variants and six missense variants, were identified in nine unrelated patients. All enrolled patients presented multiple organ defects, with the involvement of either the heart, kidney, limbs, or liver, as well as intraspinal deformities. An in vitro assay using COS-7 cells demonstrated either significantly reduced protein levels or disrupted enzymatic activity of the identified variants. Our findings demonstrated that functional variants in NADSYN1 were involved in the complex genetic etiology of CVMs and provided further evidence for the causative NADSYN1 variants in congenital NAD Deficiency Disorder.

scholarly journals Nicotinamide, Nicotinamide Riboside and Nicotinic Acid—Emerging Roles in Replicative and Chronological Aging in Yeast

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 604
Author(s):  
Ivan Orlandi ◽  
Lilia Alberghina ◽  
Marina Vai
Keyword(s):  
Nicotinic Acid ◽  
Functional Decline ◽  
Model Systems ◽  
Vitamin B3 ◽  
Proliferating Cells ◽  
Yeast Saccharomyces Cerevisiae ◽  
Nad Metabolism ◽  
Chronological Aging ◽  
Nicotinamide Riboside ◽  
Metabolic Defects

Nicotinamide, nicotinic acid and nicotinamide riboside are vitamin B3 precursors of NAD+ in the human diet. NAD+ has a fundamental importance for cellular biology, that derives from its essential role as a cofactor of various metabolic redox reactions, as well as an obligate co-substrate for NAD+-consuming enzymes which are involved in many fundamental cellular processes including aging/longevity. During aging, a systemic decrease in NAD+ levels takes place, exposing the organism to the risk of a progressive inefficiency of those processes in which NAD+ is required and, consequently, contributing to the age-associated physiological/functional decline. In this context, dietary supplementation with NAD+ precursors is considered a promising strategy to prevent NAD+ decrease and attenuate in such a way several metabolic defects common to the aging process. The metabolism of NAD+ precursors and its impact on cell longevity have benefited greatly from studies performed in the yeast Saccharomyces cerevisiae, which is one of the most established model systems used to study the aging processes of both proliferating (replicative aging) and non-proliferating cells (chronological aging). In this review we summarize important aspects of the role played by nicotinamide, nicotinic acid and nicotinamide riboside in NAD+ metabolism and how each of these NAD+ precursors contribute to the different aspects that influence both replicative and chronological aging. Taken as a whole, the findings provided by the studies carried out in S. cerevisiae are informative for the understanding of the complex dynamic flexibility of NAD+ metabolism, which is essential for the maintenance of cellular fitness and for the development of dietary supplements based on NAD+ precursors.

scholarly journals Inhibition of Kynurenine Metabolism and Its Effect in Mitochondrial Function in Hepatocellular Carcinoma

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 124-125
Author(s):  
Raul Castro-Portuguez ◽  
Samuel Freitas ◽  
George Sutphin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mitochondrial Function ◽  
De Novo ◽  
Principal Component ◽  
Kynurenine Pathway ◽  
The Cancer Genome Atlas ◽  
Wilcoxon Test ◽  
Nad Synthesis ◽  
Significant Difference ◽  
Kynurenine Metabolism

Abstract Hepatocellular carcinoma (HCC) is the most prevalent cancer in the liver. The majority of ingested tryptophan is processed in the liver through the kynurenine pathway, the endpoint of which is de novo NAD+ biosynthesis. Dysregulation of tryptophan-kynurenine metabolism and NAD+ synthesis may promote mitochondrial malfunction, tumor reprogramming, and carcinogenesis. Using a publicly available gene expression dataset from liver hepatocellular carcinoma (LIHC) samples available through The Cancer Genome Atlas (TCGA; n = 371), we employed Principal Component Analysis (PCA), hierarchical clustering, gene-pattern expression profiling, and survival analysis to cluster patients and determine overall survival. Our analysis of genes encoding kynurenine pathway enzymes determined that patients with high QPRT expression had a poor prognosis with decreased median survival, with no effect on the maximum survival. There is a significant difference in the survival between patients with high QPRT expression relative to patients with high HAAO/AFMID expression (HR = 1.2, [95% CI 0.5-1.8] P = 0.0181, Gehan-Breslow-Wilcoxon Test). Patients with high QPRT expression have higher survival rates compared with low QPRT expression (HR = 1.4, [95% CI 0.9-2.2] P = 0.0344, Gehan-Breslow-Wilcoxon Test). To test the consequences of kynurenine-pathway inhibition in mitochondrial function and morphology we use 4-Cl-3HAA, an irreversible HAAO inhibitor, and observed a small increase in mitochondrial fragmentation in HepG2 cells after 24 hours of treatment. We conclude that kynurenine metabolism may be useful as a biomarker to predict patient prognosis among HCC patients. In ongoing work, we are testing QPRT inhibitors in cell culture as a potential adjuvant for chemotherapies.

scholarly journals Equilibrative Nucleoside Transporters Mediate the Import of Nicotinamide Riboside and Nicotinic Acid Riboside into Human Cells

2021 ◽  
Vol 22 (3) ◽  
pp. 1391
Author(s):  
Andrey Kropotov ◽  
Veronika Kulikova ◽  
Kirill Nerinovski ◽  
Alexander Yakimov ◽  
Maria Svetlova ◽  
...  
Keyword(s):  
Nicotinic Acid ◽  
Mammalian Cells ◽  
Experimental Models ◽  
The Body ◽  
Nucleoside Transporters ◽  
Hek293 Cells ◽  
Nucleoside Transporter ◽  
Vitamin B3 ◽  
Animal Cells ◽  
Nicotinamide Riboside

Nicotinamide riboside (NR), a new form of vitamin B3, is an effective precursor of nicotinamide adenine dinucleotide (NAD+) in human and animal cells. The introduction of NR into the body effectively increases the level of intracellular NAD+ and thereby restores physiological functions that are weakened or lost in experimental models of aging and various pathologies. Despite the active use of NR in applied biomedicine, the mechanism of its transport into mammalian cells is currently not understood. In this study, we used overexpression of proteins in HEK293 cells, and metabolite detection by NMR, to show that extracellular NR can be imported into cells by members of the equilibrative nucleoside transporter (ENT) family ENT1, ENT2, and ENT4. After being imported into cells, NR is readily metabolized resulting in Nam generation. Moreover, the same ENT-dependent mechanism can be used to import the deamidated form of NR, nicotinic acid riboside (NAR). However, NAR uptake into HEK293 cells required the stimulation of its active utilization in the cytosol such as phosphorylation by NR kinase. On the other hand, we did not detect any NR uptake mediated by the concentrative nucleoside transporters (CNT) CNT1, CNT2, or CNT3, while overexpression of CNT3, but not CNT1 or CNT2, moderately stimulated NAR utilization by HEK293 cells.

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