This article was originally published in the Encyclopedia of Biological Chemistry published by Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the author's institution, for non-commercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who you know, and providing a copy to your institution’s administrator.

All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier's permissions site at:

http://www.elsevier.com/locate/permissionusematerial

Bogan K.L., and Brenner C. (2013) Biochemistry: Niacin/NAD(P). In: Lennarz W.J. and Lane M.D. (eds.) The Encyclopedia of Biological Chemistry, vol. 1, pp. 172-178. Waltham, MA: Academic Press.

© 2013 Elsevier Inc. All rights reserved. Author's personal copy

Biochemistry: Niacin/NAD(P)

K L Bogan and C Brenner, The University of Iowa, Iowa City, IA, USA

ã 2013 Elsevier Inc. All rights reserved.

Glossary Pellagra Niacin-deficient nutritional condition. þ þ + Nicotinoproteins NAD - or NADP -dependent Poly(ADPribose) polymerase NAD -dependent oxidoreductases that bind the coenzymes tightly as enzyme that forms protein linked or unlinked chains

prosthetic groups. of ADPribose. þ Oxidoreductase A coenzyme-dependent hydride Sirtuin NAD -dependent protein lysine deacetylase transfer enzyme. related to yeast Sir2.

Nicotinamide Adenine Dinucleotide History and nicotinamide riboside (NR). These water-soluble vitamins are þ Structure NAD breakdown products and metabolites that are trans- ported systemically; these are available in the diet (Figure 2(a)). þ Nicotinamide adenine dinucleotide (NAD ) was at the center NA is utilized by the Preiss–Handler pathway, which of some of the greatest discoveries in the biological sciences in involves three enzymatic steps through nicotinic acid mono- the early twentieth century. Originally termed cozymase or nucleotide (NaMN) and nicotinic acid adenine dinucleotide codehydrogenase I and later diphosphopyridine nucleotide (NaAD). In vertebrates, Nam is utilized in two enzymatic (DPN), the activity was described in 1905 as a component of steps through nicotinamide mononucleotide (NMN). Since yeast extracts that accelerated cell-free alcoholic fermentation. Nam can be converted into NA in many bacteria by a nicoti-

Arthur Harden and William Young discovered that glycolysis namidase not encoded in vertebrate genomes, Nam entry proceeded slowly until a heat-stable and dialyzable cozymase into the Preiss–Handler pathway in vertebrates is thought þ fraction was added, which we now know contained NAD , to depend on bacterial nicotinamidase in the gut. NR can be þ þ þ adenosine triphosphate (ATP), and Mg2 . The NAD compo- converted into two steps to NAD through NMN, or can be þ nent was later purified by Harden and Hans von Euler. In 1936, converted into NAD via splitting the nucleoside followed by þ the structure of NAD was determined independently by Otto Nam salvage. Specific transporters have been identified for Warburg and von Euler, and a role in oxidative metabolism was the uptake of NA and NR, but not Nam or nicotinic acid þ defined. Codehydrogenase II was found to be a triphosphopyr- riboside (NAR), an NAD metabolite that can also be utilized idine dinucleotide, that is, nicotinamide adenine dinucleotide byyeastathighdoses. þ þ þ phosphate (NADP ). Two salvageable precursors of NAD , Most organisms synthesize NAD from either tryptophan De novo nicotinic acid (NA) and nicotinamide (Nam), were identified or aspartic acid. synthesis nearly always proceeds by Conrad Elvehjem in a search for non protein fractions from through quinolinic acid (QA) and NaMN, at which point þ the liver that would reverse black spots on the tongues of dogs, NAD is produced by the last two enzymes of the Preiss– an induced nutritional deficiency similar to pellagra, which was Handler pathway (Figure 3). þ an epidemic in the American South in the early 1900s. Later, the The phosphorylated forms of NAD are also generated by þ þ basis for both de novo synthesis of NAD from amino acids and specific enzyme activities (Figure 2(b)). NADP is generated þ þ þ salvage synthesis of NAD was worked out. NA and Nam were from NAD by NAD kinase (NADK). In yeast, a mitochon- collectively termed ‘niacins’. The broad use of niacin supple- drial NADH kinase generates NADPH from NADH. In addi- mentation has virtually eliminated pellagra. tion, in bacteria and in animal mitochondria, the proton þ NAD is so termed because it consists of a Nam nucleotide, translocating, membrane-bound NADPH transhydrogenase 0 þ þ that is, nicotinamide riboside 5 -monophosphate, joined to interconverts NADPH and NAD into NADP and NADH. the phosphate of an adenine nucleotide, that is., adenosine Thus, NADK activity is a gatekeeper of both phosphorylated 0 þ þ 5 -monophosphate. NADP is formed when a phosphate group forms of NAD , and NADPH transhydrogenase allows a cell to þ is added to the 20 position of adenosine (Figure 1). The glyco- maintain a redox balance in which NAD levels exceed NADH þ sidic linkages between bases and ribosyl moieties are b in both levels, while NADPH levels exceed those of NADP . nucleotides. The hydride-accepting moiety is the Nam base such þ þ that the plus signs on NAD and NADP refer to the oxidized, þ þ hydride-accepting forms. The overall charge of these molecules NAD and NADP in Redox Metabolism is negative because of the phosphates. Electron transfers that occur in oxidation–reduction (redox) reactions are essential to metabolism and life in all organisms.

Salvage and De Novo Pathways Redox reactions are catalyzed by a large family of enzymes called ‘oxidoreductases’. The electron-donating species in a þ All dividing cells either form NAD de novo from an ami- redox reaction is referred to as the reducing agent, or reductant, þ no acid and/or resynthesize NAD from NA, Nam, and/or and the electron-accepting species is the oxidizing agent, or

172 Encyclopedia of Biological Chemistry, (2013), vol. 1, pp. 172-178

Author's personal copy

Metabolism Vitamins and Hormones | Biochemistry: Niacin/NAD(P) 173

b-NAD+ b-NADH

Oxidized form Reduced form

NH 2 O HH O N N Nicotinamide NH2

- + :H NH2 N N N O O O O OOP OP N - - O O HO OH XO OH ADPribose ADPribose

ADP NR

AMP NMN

X = H NAD+

X =PO2-NADP+ 3 þ þ þ Figure 1 NAD /NADH and NADP /NADPH structure. NAD is a dinucleotide consisting of a nicotinamide nucleotide, that is, nicotinamide riboside 50-monophosphate (NMN) joined to the phosphate of an adenine nucleotide, that is, adenosine 50-monophosphate (AMP). In NADþ, the X in the 0 þ 2 position of the adenosine is an H, whereas in NADP , a phosphate group is in the X position. The glycosidic linkages between bases and ribosyl þ þ moieties are b in both nucleotides. The Nam base is the hydride-accepting moiety, such that the plus signs on NAD and NADP refer to the oxidized, hydride-accepting forms.

oxidant. In biological redox reactions, the movement of elec- 20-hydroxyl group of the adenine nucleotide. This site also þ trons often occurs concomitant with the loss of hydrogen. This helps to distinguish enzymes that bind NAD from those þ species is referred to as a hydride ion (:H–). that bind NADP , as this residue is uncharged in enzymes þ þ þ In NAD -dependent dehydrogenation reactions, NAD that bind NADP in order to accommodate the 20-phosphate þ þ and NADP undergo reduction of the nicotinamide ring to that takes the place of the hydroxyl. In NADP -binding form NADH and NADPH, respectively (Figure 1). In such enzymes, the phosphate interacts with a nearby arginine resi- reactions, a hydride ion is transferred to the carbon at the due instead. The phosphate-binding glycine-rich sequence þ fourth position of the nicotinamide ring of NAD (Figure 1). (GXGXXG) resides in a loop between the first a-helix and This transfer of hydride can happen in two ways. In A-type b-strand. The first and second glycines are thought to allow oxidoreductases, the hydrogen is transferred from above the important turns of the main chain in this loop. These turns plane of the nicotinamide ring to the front of the nicotinamide promote an interaction between the main chain and the þ ring (A side), while B-type oxidoreductases transfer of the atom diphosphate bridge of NAD to occur (Figure 4(b)). The occurs from below to the backside of the nicotinamide ring third glycine promotes tight packing in the nucleotide-binding þ þ þ (B side). This depends on how NAD is oriented within the domain that prohibits NADP from binding. NADP -binding nucleotide-binding domain of the enzyme. enzymes have a larger amino acid (alanine, serine, or proline) þ Oxidoreductases bind the NAD(P) dinucleotide in a struc- in the place of the glycine, which disrupts the close packing þ tural motif termed as a Rossmann fold (Figure 4(a)). The core and allows NADP to bind. Finally, the hydrophobic core, Rossman fold consists of one nucleotide-binding domain which contains six small hydrophobic amino acids, is neces- constructed from at least three b-strands flanked by two a- sary for maintaining the proper packing of the b-strands with helices (babab ), though some oxidoreductases have addi- respect to the a-helices. While these motifs form the proper tional b-strands. There are four important motifs found tertiary structure and interactions to specify binding of þ þ within the Rossmann fold: a conserved positively charged NAD versus NADP , some enzymes, such as aldose reductase, residue (Arg or Lys) at the beginning of the first b-strand, a glucose-6-phosphate dehydrogenase, and methylenetetrahy- conserved negatively charged residue (Glu or Asp) at the drofolate reductase, are exceptions to the rule, and bind both þ þ end of the second b-strand, a phosphate-binding sequence – NAD and NADP . GXGXXG– and six conserved positions occupied by small For the majority of enzymes that do show a high level of þ þ hydrophobic amino acids. specificity for either NAD or NADP , the preference often þ Three of four conserved motifs within the Rossmann fold reflects the distinct metabolic role of the enzyme. NAD is have well-defined nucleotide-binding, structural, or catalytic typically utilized in catabolic pathways in which energy is functions. The conserved positively charged residue (Arg or liberated from the oxidation of substrate molecules, whereas þ Lys) found at the beginning of the first b-strand is not well NADP is most commonly utilized in anabolic reactions such understood. It is thought to participate in stabilizing interac- as fatty acid synthesis and photosynthesis. The ratios of oxi- þ þ tions with nearby b-strands, though these are not fully char- dized to reduced forms of NAD and NADP reflect these acterized. The conserved negatively charged residue at the activities as well. In most tissues, in which it has been measured, þ þ carboxyl terminus of the second b-strand is used to bind the the ratio of NAD to NADH is high, providing ample NAD to

Encyclopedia of Biological Chemistry, (2013), vol. 1, pp. 172-178

Author's personal copy

174 Metabolism Vitamins and Hormones | Biochemistry: Niacin/NAD(P)

QA NaMN O NaAD O NaD+ O NMN O

COOH QPRT - - O O NH2 NH EC 2.4.2.19 2

NaMNAT NADS NMNAT N + + + + Ј COOH N EC 2.7.7.18 N EC 6.3.5.1 N EC 2.7.7.1 N 5 -Nucleotidase EC 3.1.3.5 5Ј-Nucleotidase Pribo ADPribo ADPribo Pribo

EC 3.1.3.5 NRK NAD-consuming NRK EC 2.7.1.22 NAPRT reactions EC 2.7.1.22 EC 2.7.1.22 NamPRT EC 2.4.2.12 O O Nam O O NAR NA NR

- - O O NH2 NH PNP 2 EC 2.4.2.1 PNP Bacterial/fungal URH + N EC 2.4.2.1 N N + N nicotinamidase EC 3.2.2.3 EC 3.5.1.19 Ribo Ribo

(a) Import Import

NAD+ NADP+ NADK EC 2.7.1.23

Oxidoreductase Oxidoreductase

NADH NADPH NADHK EC 2.7.1.86

+ NADP NAD+ NADPH transhydrogenase (b) EC 1.6.1.2 þ þ þ Figure 2 NAD and NADP generation. (a) Cells have evolved pathways to salvage the pyridine ring of NAD from precursors NA, Nam, and NR, each of which is produced in the cell as metabolites and obtained in the diet as vitamins. Nicotinic acid (NA) is utilized by what is termed as the Preiss–Handler pathway, which involves three enzymatic steps. First, NA is converted into nicotinic acid mononucleotide (NaMN) by the nicotinic acid phosphoribosyltransferase enzyme (NAPRT). NaMN is subsequently converted into nicotinic acid adenine dinucleotide (NaAD), also called desamido NAD þ, by nicotinamide mononucleotide adenylyl transferase enzymes (NMNAT). Finally, NaAD is converted into NADþ by the NADþ synthetase enzyme (NADS). In mammals, salvaged Nam is utilized by a nicotinamide phosphoribosyltransferase enzyme (NamPRT). NamPRT catalyzes the addition of a phosphoribose moiety onto Nam forming nicotinamide mononucleotide (NMN). NMN is then converted into NADþ by the NMNAT enzymes. Nam utilization differs among species. In some bacteria and fungi, Nam is converted into NA by a nicotinamidase enzyme þ (dotted line), after which it is utilized through the Priess–Handler pathway to form NAD . NR can be utilized through two distinct pathways. In an

Nrk-dependent pathway, it is phosphorylated by nicotinamide riboside kinases (NRKs) to form NMN, which is converted into NADþ by NMNAT enzymes. Alternatively, NR is utilized by purine nucleoside phosphorylase (PNP), which converts NR into Nam. Specific transporters have been þ identified that are responsible for the uptake of NA and NR. Another NAD precursor, that is not efficiently imported, but that can be produced intracellularly, is nicotinic acid riboside (NAR). NAR is phosphorylated by NRK to form NaMN, and is hydrolyzed to NA by PNP. Data in yeast 0 þ Saccharomyces cerevisiae indicate that NR and NAR are generated by the activities of NMN/NaMN 5 -nucleotidases. (b) NADP and NADPH þ þ þ are generated from NAD and NADH by kinases (NADK and NADHK). NADPH transhydrogenase interconverts NADPH and NAD into NADP and NADH.

accept hydride ions from substrates, whereas the level of acids, and a-keto acids), while NADPH serves as a reductant for þ NADP is often significantly lower than NADPH promoting fatty acid synthesis in the cytosol. þ hydride transfer to substrate molecules from NADPH, as occurs Hydride transfer from substrate to NAD has three prere- in anabolic pathways. Likewise, the organelles in which these quisites. First, the substrate must have high electron density on cofactors are primarily used are also distinct and reflective of the carbon that donates the hydride. This is often ensured by þ their different activities. NAD is most often utilized in the interactions of the substrate with active site residues in redox þ mitochondria for oxidation of fuel molecules (pyruvate, fatty enzymes. Similarly, the C4 carbon of the Nam ring of NAD ,

Encyclopedia of Biological Chemistry, (2013), vol. 1, pp. 172-178

Author's personal copy

Metabolism Vitamins and Hormones | Biochemistry: Niacin/NAD(P) 175

L-Tryptophan N-Formyl-kynurenine L-Kynurenine

O NH2 O NH2 IDO Arylformamidase NH 2 EC 1.13.11.42 C EC 3.5.1.9 C

TDO COOH COOH

COOH EC 1.13.11.11

N H HN CHO NH2

Kynurenine (a) 3-monooxygenase EC 3.5.1.9

O NH2

COOH COOH C COOH

3-Hydroxy-anthranilate Kynureninase 3,4-dioxygenase N EC 3.7.1.3 N NH NH2 COOH EC 1.13.11.6 2 OH

Quinolinate 3-Hydroxy-anthranilic acid 3-Hydroxy-L-kynurenine

(b)

H H H N 2 2 2 C HN C OH OH COOH CH C C C

L-Aspartate Quinolinate O C O O C O oxidase synthase N OH EC 1.4.3.16 OH EC 2.5.1.72 COOH

L-Aspartate Iminoaspartate Quinolinate

(c)

Figure 3 De novo biosynthetic pathways. (a) Present in most eukaryotic systems, the de novo pathway from tryptophan synthesizes quinolinic acid (QA) in five enzymatic steps. In the first step, tryptophan is converted into N-formyl-kynurenine by either indoleamine 2,3 deoxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO). Formylkynurenine is subsequently converted into L-kynurenine by kynurenine formamidase (KFase). Kynurenine- 3-hydrolase (K3H) produces 3-hydroxykyninurenine from L-kynurenine, which is then a substrate of kynureninase (Kyase) to produce 3-hydroxy anthranilic acid. 3-Hydroxyanthranilate 3,4-dioxygenase (3HAO) then converts 3-hydroxyanthranilic acid into 2-amino-3-carboxy-muconate semialdehyde, which is converted into quinolinic acid by spontaneous cyclization. (b) Present in most prokaryotic systems, the de novo pathway from aspartic acid synthesizes QA in two enzymatic steps. Aspartate is converted into iminoaspartate by L-aspartate oxidase (AO), which is subsequently converted into QA by quinolinate synthase (QS).

which accepts the hydride ion, must have sufficiently low elec- but stay tightly bound. Enzymes that catalyze reactions using a tron density to accept the hydride ion. Finally, the Nam moiety prosthetic group often have higher turnover rates than þ of NAD must be positioned close enough to the hydride- enzymes that allow the coenzyme to dissociate by virtue of donating species on the substrate to accept it. This is accom- eliminating slow association and dissociation steps. In addi- þ plished by the specific binding of NAD in the Rossmann fold. tion, enzymes that bind and sequester a cofactor in the active For example, the active site of lactate dehydrogenase (LDH), an redox state are rendered insensitive to regulation due to the

A-type oxidoreductase, utilizes an active site residue, histidine- redox state of the cell. This is due to the enzyme’s ability

195, as a general base. In catalysis, the histidine residue removes to return the bound coenzyme to its original active redox a proton from the hydroxyl group of the alcohol substrate state after catalysis so that it can perform subsequent reactions. promoting the hydride transfer from the hydroxyl group to the Enzymes accomplish this in several ways. First, the enzyme can C4 position of the Nam moiety (Figure 5). Importantly, these participate in alternating oxidation and reduction reactions mechanisms both avoid actual formation of the hydride ion, with different substrates. Alternatively, the bound coenzyme which is highly reactive, and cannot exist in water. can be reoxidized or reduced by a nonsubstrate molecule, such as ferrodoxin. In other reactions, the coenzyme can tran- siently oxidize or reduce a substrate, but return to the original þ NAD as a Prosthetic Group for Enzymes redox state prior to product release. Finally, in some reactions, the coenzyme can accept only a pair of electrons and not the þ In contrast to the reversible binding behavior of NAD co- entire hydride ion. In this way, the bound coenzyme can enzymes in redox reactions, these cofactors can also function promote catalysis without full oxidation or reduction occur- þ as tightly bound prosthetic groups. In such enzymes, NAD ring, eliminating the regeneration requirement. Enzymes that þ þ þ and NADP do not dissociate with the release of the product, bind NAD and NADP as prosthetic groups are termed

Encyclopedia of Biological Chemistry, (2013), vol. 1, pp. 172-178

Author's personal copy

176 Metabolism Vitamins and Hormones | Biochemistry: Niacin/NAD(P)

(a) (b)

Figure 4 The structure of lactate dehydrogenase (LDH). (a) The structure of LDH (PDB entry 2JC9) highlighting the Rossmann fold in green. (b) A close-up of the Rossman fold illustrating the critical residues and the interactions with NADþ.

CH

CH2

His 195 O

NH NH2

N

ADPribose H +N H O

H3C

O O–

Lactate

Figure 5 Dehydrogenation mechanism of LDH. His 195 acts as a general base to promote hydride transfer to the nicotinamide ring.

þ ‘nicotinoproteins’, which belong to a superfamily of metallo activities, which transfer and/or polymerize NAD -derived alcohol dehydrogenases. ADPribose to target molecules. PARP activity, which is consid- þ ered one of the major NAD -consuming activities within the

cell, is upregulated in response to genome damage. Individual Nonredox Roles members of the PARP family have been shown to mediate diverse cellular responses including inflammation, intracellu- þ In addition to its coenzymatic functions, NAD is a consumed lar trafficking, and cell death. þ substrate of multiple families of enzymes (Figure 6). Generally A second class of NAD -consuming enzymes consists of termed as glycohydrolases, these enzymes cleave the glycosidic cyclic (ADPribosyl) synthases, which are largely extracellular þ bond between the nicotinamide and adenosine diphosphate enzymes that consume NAD to produce and hydrolyze cyclic- þ (ADP)ribose moieties of NAD . ADPribose. These activities are particularly important for cal- þ þ One class of NAD -consuming enzymes possesses ADPribose cium (Ca2 ) regulation within the cell, as cyclic-ADPribose is a þ transferase (ART) and poly(ADPribose) polymerase (PARP) potent Ca2 -mobilizing second messenger.

Encyclopedia of Biological Chemistry, (2013), vol. 1, pp. 172-178

Author's personal copy

Metabolism Vitamins and Hormones | Biochemistry: Niacin/NAD(P) 177

NAD+

ADPribosyl transferase Sirtuins

ADPribosylated Poly (ADPribose)

proteins + Nam polymerase ADPribosyl Deacetylated proteins + cyclase Ac-ADPribose + Nam cADPribose Poly (ADPribosyl) ated proteins + Nam þ þ Figure 6 Nonredox roles of NAD . Enzymes that cleave the glycosidic bond between the nicotinamide and ADPribose moieties of NAD are termed þ glycohydrolases. These include ADPribose transferase (ART) and poly(ADPribose) polymerase (PARP) activities, which attach NAD -derived ADPribose to target molecules, and cyclic ADPribosyl synthases, which consume NADþ to produce and hydrolyze cyclic-ADPribose. In addition, þ sirtuins catalyze NAD -dependent protein lysine deacetylation by conversion of a lysine-acetylated peptide to a deacetylated peptide with production 0 of 2 -O-acetyl-ADPribose and Nam as products.

þ A third class of NAD -consuming enzymes is sirtuins, the therapy of neurodegenerative diseases, such as Alzheimer’s and þ NAD -dependent protein lysine deacetylases related to yeast Parkinson’s disease. þ Sir2. These enzymes convert a lysine-acetylated peptide into a Many of the enzymes that use NAD either as a co-enzyme 0 deacetylated peptide with the production of 2 -O-acetyl-ADPri- or as a substrate are considered as potential targets for drug þ bose and Nam as products. This process has been implicated in design. Although redox enzymes bind NAD in a conserved gene regulation, enzyme activity, and longevity. binding pocket, enzyme-specific inhibitors based on the struc- þ ture of NAD have been developed. For example, the nucleo-

side analog tiazofurin, which is converted in the cell into a þ þ NAD Alterations in Aging toxic analog of NAD , tiazofurin adenine dinucleotide, is a potent prodrug inhibitor of IMP dehydrogenase (IMPDH), an de novo Calorie restriction (CR) is a powerful means to extend life span enzyme important in purine synthesis that might be targeted in malignancies, viral infection, and/or for the pur- in model organisms. In yeast, Sir2 plays a role in mediating the þ poses of immunosuppression. effect of CR on extension of life span. Since NAD is involved in þ NAD biosynthetic pathways have also been targeted, espe- glucose utilization and is an essential Sir2 substrate, its metab- þ olism is one potential subsystem that may be altered by CR. cially for antibiotic development. The differences in NAD Among the proposed mechanisms, it is conceivable that the biosynthetic pathways and enzymes between humans and þ þ lower organisms make the development of specific inhibitors NAD /NADH ratio, the NAD /Nam ratio, altered flux, and/or þ to block NAD synthesis in infectious organisms a plausible increased net synthesis may regulate sirtuin activities. PARP activities may also influence the aging process in an path to antibiotics. So far, drugs of this nature have been used þ Mycobacterium tuberculosi NAD -dependent manner. In particular, the DNA-damage sur- to target s, the tuberculosis-causing bac- veillance activity of PARP has been proposed as a critical factor terium. Isonicotinylhydrazine is a Nam-related anti-tuberculosis to reduce genotoxic stress, maintain genomic stability, and agent that is metabolized to form inhibitors of redox enzymes. It is anticipated that additional agents will be developed against promote cellular survival. PARP family enzymes, tankyrase-1 and tankyrase-2, are also involved in the maintenance of telo- genetically validated enzymes, potentially using structure-based mere length, which has been implicated in the regulation of drug design and/or high-throughput screening. aging. Roles in aging and telomere maintenance are under- See also: scored by the observation that PARP-1, tankyrase-1, and Bioenergetics: Bioenergetics: General Definition of tankyrase-2 interact with the Werner syndrome protein, Principles; Calcium Signaling by Cyclic ADP-Ribose and NAADP; which is altered in progeric humans. Nicotinamide Nucleotide Transhydrogenase.

Further Reading Human Health and Disease Bellamacina CR (1996) The nicotinamide dinucleotide binding motif: A comparison of Widespread use of niacins has largely eliminated pellagra, nucleotide binding proteins. FASEB Journal 10: 1257–1269. whereas high-dose NA is widely used for dyslipidemia and Bogan KL and Brenner C (2008) Nicotinic acid, nicotinamide and nicotinamide riboside: þ high-dose Nam has been tested for efficacy in stroke and A molecular evaluation of NAD precursor vitamins in human nutrition. Annual Review of Nutrition 28: 115–130. other conditions. Since high-dose NA causes a flushing response þ Bogan KL, Evans C, Belenky P, et al. (2009) Identification of Isn1 and Sdt1 as and high-dose Nam may inhibit sirtuins and other NAD - glucose- and vitamin-regulated nicotinamide mononucleotide and nicotinic acid consuming enzymes, NR is being tested for effectiveness in the adenine mononucleotide 5’-nucleotidases responsible for production of

Encyclopedia of Biological Chemistry, (2013), vol. 1, pp. 172-178

Author's personal copy

178 Metabolism Vitamins and Hormones | Biochemistry: Niacin/NAD(P)

nicotinamide riboside and nicotinic acid riboside. Journal of Biological Chemistry Nelson DL and Cox MM (2008) Biological oxidation–reduction reactions. In: Lehninger 284: 34861–34869. Principles of Biochemistry, 5th edn., chapter 13, pp. 512–526. New York, NY: Gazzaniga F, Stebbins R, Chang SZ, McPeek MA, and Brenner C (2009) Microbial NAD WH Freeman. þ þ metabolism: Lessons from comparative genomics. Microbiology and Molecular Oppenheimer NJ (2010) NAD and NADP as prosthetic groups for enzymes. Biology Reviews 73: 529–541. In: Encyclopedia of Life Sciences, doi:10.1002/9780470015902.a000637.pub2. Longo VD (2009) Linking sirtuins, IGF-I signaling and starvation. Experimental Chichester: Wiley. Gerontology 44: 70–74. Ziegler M (2001) New functions of a long-known molecule: Emerging roles of þ Magni G, Amici A, Emanuelli M, et al. (2004) Enzymology of NAD homeostasis in NAD in cellular signaling. European Journal of Biochemistry man. Cellular and Molecular Life Sciences 61: 19–34. 267: 1550–1564.

Encyclopedia of Biological Chemistry, (2013), vol. 1, pp. 172-178