NAD+ metabolism in health and disease

doi:10.1016/j.tibs.2006.11.006

Trends in Biochemical Sciences

Volume 32, Issue 1, January 2007, Pages 12-19

https://doi.org/10.1016/j.tibs.2006.11.006 Get rights and content

Nicotinamide adenine dinucleotide (NAD⁺) is both a coenzyme for hydride-transfer enzymes and a substrate for NAD⁺-consuming enzymes, which include ADP-ribose transferases, poly(ADP-ribose) polymerases, cADP-ribose synthases and sirtuins. Recent results establish protective roles for NAD⁺ that might be applicable therapeutically to prevent neurodegenerative conditions and to fight Candida glabrata infection. In addition, the contribution that NAD⁺ metabolism makes to lifespan extension in model systems indicates that therapies to boost NAD⁺ might promote some of the beneficial effects of calorie restriction. Nicotinamide riboside, the recently discovered nucleoside precursor of NAD⁺ in eukaryotic systems, might have advantages as a therapy to elevate NAD⁺ without inhibiting sirtuins, which is associated with high-dose nicotinamide, or incurring the unpleasant side-effects of high-dose nicotinic acid.

Section snippets

The biology and biosynthesis of NAD⁺

Nicotinamide adenine dinucleotide (NAD⁺) and its phosphorylated and reduced forms, NADP⁺, NADH and NADPH, have central roles in cellular metabolism and energy production as hydride-accepting and hydride-donating coenzymes. Discovery of the coenzymatic activity of NAD⁺ is reviewed in Box 1 and the redox chemistry that is mediated by NAD⁺ is schematized in Figure 1. Such reactions are not destructive in the sense that NAD⁺ and NADH are interconverted by hydride transfer. As with all

Three classes of NAD⁺ consumers

The abundance of NAD⁺ is also regulated by breakdown, largely because the molecule is not only coenzyme for oxidoreductases but also a substrate for three classes of enzymes that cleave NAD⁺ to produce Nam and an ADP-ribosyl product. Although, historically, these enzymes have been called NAD⁺ glycohydrolases, NAD⁺-dependent ADP-ribosyl transferase is a more precise term [5]. However, to avoid confusion with dedicated protein mono(ADP-ribosyl) transferases, we refer to the enzymes historically

Nam metabolism, and intracellular and extracellular NAD⁺

A common theme among NAD⁺ consumers is inhibition by Nam. ART, PARP [20], CD38 [21] and sirtuin [22] enzymes each contain a Nam-product site that can be occupied in the presence of substrates and enzyme intermediates. Thus, each enzyme can be inhibited by Nam, which effectively drives the formation of base-exchanged substrates. Because of this type of product inhibition, the salvage and/or elimination of Nam are crucial steps in NAD⁺ metabolism.

Whereas Nam is salvaged to Na in fungi and many

NAD⁺ synthesis in neuroprotection

Damage to nerve fibers leads to a series of molecular and cellular responses that are termed Wallerian degeneration or axonopathy. Axonopathy is a critical early event in distinct degenerative conditions including Alzheimer's disease (AD), Parkinson's disease and multiple sclerosis (MS), and it occurs in response to infections, alcoholism, acute chemotherapy-associated toxicity, diabetes and normal aging [33]. The Wallerian degeneration slow (wld^s) mouse is a spontaneous mutant that contains an

NAD⁺ synthesis in candidiasis

Candida glabrata, the second leading cause of candidiasis, is a fungus with an interesting variation in NAD⁺ metabolism. Saccharomyces cerevisiae NAD⁺ metabolism differs from that of humans because the yeast lacks ARTs, PARPs and cADP-ribose synthases, and contains nicotinamidase (Pnc1) rather than PBEF. The C. glabrata genome is additionally missing genes for the de novo biosynthesis of NAD⁺, such that it is a Na auxotroph [41]. Just as S. cerevisiae Sir2 represses transcription of

NAD⁺ synthesis in the regulation of aging

All fungi and animals that have been examined have characteristic rates of aging that depend on environmental conditions and yield mutations that confer either progeric or long-lived phenotypes. Calorie restriction (CR) is the most powerful intervention known to extend the lifespan of yeasts, worms, flies and mammals (Reviewed in [46]). CR increases lifespan and delays the onset of distinct debilitating diseases in different models. CR reduces carcinogenesis in mouse models, prevents kidney

Na and plasma lipids

Finally, it is important to reinvestigate the mechanisms by which Na reduces levels of triglycerides and low-density lipoprotein cholesterol and elevates HDL cholesterol. It has long been assumed that the beneficial effects of Na on plasma lipids are mediated via a receptor rather than a vitamin mechanism because of the high dose required (100-fold higher than that required to prevent pellagra) and the failure of Nam to provide similar benefits [72]. Today, however, low HDL cholesterol and poor

Concluding remarks

The first century of NAD⁺ research has been punctuated by multiple discoveries. Elucidation of the essential role of NAD⁺ in glycolysis was followed by discoveries in human nutrition and coenzyme biosynthesis. In recent years, the role of NAD⁺ in protein deacetylation has been discovered. NAD⁺ precursors have been used to protect severed axons from degeneration, ameliorate neuromuscular deficits in a mouse model of MS and reduce the severity of candidiasis in a mouse model. Studies are needed

Glossary

Ecto-enzymes: membrane-bound enzymes with an extracellular active-site.
Flushing: a painful condition that consists of ‘hot flashes’, reddening and heat in the extremities.
Reverse cholesterol transport: the multi-step process by which HDL particles deliver cholesterol to the liver for excretion through bile acids.
Salvage and de novo biosynthesis: biosynthetic pathways are termed salvage if the distinctive piece of the final product is recovered from breakdown products and de novo if the distinctive

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Cyclooxygenase-2 (COX-2) is an inducible enzyme responsible for prostaglandin synthesis during inflammation and immune responses. Our previous results show that NAD⁺ level decreased in activated macrophages while nicotinamide mononucleotide (NMN) supplementation suppressed the inflammatory responses via restoring NAD⁺ level and downregulating COX-2. However, whether NMN downregulates COX-2 in mouse model of inflammation, and its underlying mechanism needs to be further explored. In the present study, we established LPS- and alum-induced inflammation model and demonstrated that NMN suppressed the inflammatory responses in vivo. Quantitative proteomics in mouse peritoneal macrophages identified that NMN activated AhR signaling pathway in activated macrophages. Furthermore, we revealed that NMN supplementation led to IDO1 activation and kynurenine accumulation, which caused AhR nuclear translocation and activation. On the other hand, AhR or IDO1 knockout abolished the effects of NMN on suppressing COX-2 expression and inflammatory responses in macrophages. In summary, our results demonstrated that NMN suppresses inflammatory responses by activating IDO-kynurenine-AhR pathway, and suggested that administration of NMN in early-stage immuno-activation may cause an adverse health effect.
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^*

Disclosure statement

C.B. is inventor of intellectual property related to nicotinamide riboside kinases and uses of nicotinamide riboside. The intellectual property is owned by C.B.'s employer, Trustees of Dartmouth College, and therapeutic uses are licensed by Sirtris Pharmaceuticals, a firm for which C.B. serves on the Scientific Advisory Board.

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Trends in Biochemical Sciences

ReviewNAD+ metabolism in health and disease

Section snippets

The biology and biosynthesis of NAD+

Three classes of NAD+ consumers

Nam metabolism, and intracellular and extracellular NAD+

NAD+ synthesis in neuroprotection

NAD+ synthesis in candidiasis

NAD+ synthesis in the regulation of aging

Na and plasma lipids

Concluding remarks

Glossary

Cell

J. Biol. Chem.

J. Biol. Chem.

Pharmacol. Res.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Int. J. Med. Microbiol.

J. Cell Biol.

Biochem. Biophys. Res. Commun.

Am. J. Cardiol.

J. Biol. Chem.

Mech. Ageing Dev.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

Ribosylnicotinamide kinase domain of NadR protein: identification and implications in NAD biosynthesis

J. Bacteriol.

The biochemistry of sirtuins

Annu. Rev. Biochem.

Poly(ADP-ribose): novel functions for an old molecule

Nat. Rev. Mol. Cell Biol.

Synthesis and degradation of cyclic ADP-ribose by NAD glycohydrolases

Science

Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38

Science

Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

Nature

Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose

Proc. Natl. Acad. Sci. U. S. A.

Chemistry of gene silencing: the mechanism of NAD+-dependent deacetylation reactions

Biochemistry

A chromosomal SIR2 homologue with both histone NAD-dependent ADP-ribosyltransferase and deacetylase activities is involved in DNA repair in Trypanosoma brucei

EMBO J.

Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage

Cell Cycle

The reaction mechanism for CD38. A single intermediate is responsible for cyclization, hydrolysis, and base-exchange chemistries

Biochemistry

Review
NAD⁺ metabolism in health and disease

The biology and biosynthesis of NAD⁺

Three classes of NAD⁺ consumers

Nam metabolism, and intracellular and extracellular NAD⁺

NAD⁺ synthesis in neuroprotection

NAD⁺ synthesis in candidiasis

NAD⁺ synthesis in the regulation of aging