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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.

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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.

GlossaryNicotinoproteins NADþ- or NADPþ-dependentoxidoreductases that bind the coenzymes tightly as

prosthetic groups.

Oxidoreductase A coenzyme-dependent hydride

transfer enzyme.

Pellagra Niacin-deficient nutritional condition.

Poly(ADPribose) polymerase NAD+-dependent

enzyme that forms protein linked or unlinked chains

of ADPribose.

Sirtuin NADþ-dependent protein lysine deacetylase

related to yeast Sir2.

17
2Encyclopedia of Biological Chem
Nicotinamide Adenine Dinucleotide History andStructure

Nicotinamide adenine dinucleotide (NADþ) was at the center

of some of the greatest discoveries in the biological sciences in

the early twentieth century. Originally termed cozymase or

codehydrogenase I and later diphosphopyridine nucleotide

(DPN), the activity was described in 1905 as a component of

yeast extracts that accelerated cell-free alcoholic fermentation.

Arthur Harden and William Young discovered that glycolysis

proceeded slowly until a heat-stable and dialyzable cozymase

fraction was added, which we now know contained NADþ,adenosine triphosphate (ATP), and Mg2þ. The NADþ compo-

nent was later purified by Harden and Hans von Euler. In 1936,

the structure of NADþ was determined independently by Otto

Warburg and von Euler, and a role in oxidative metabolismwas

defined. Codehydrogenase II was found to be a triphosphopyr-

idine dinucleotide, that is, nicotinamide adenine dinucleotide

phosphate (NADPþ). Two salvageable precursors of NADþ,nicotinic acid (NA) and nicotinamide (Nam), were identified

by Conrad Elvehjem in a search for non protein fractions from

the liver that would reverse black spots on the tongues of dogs,

an induced nutritional deficiency similar to pellagra, which was

an epidemic in the American South in the early 1900s. Later, the

basis for both de novo synthesis of NADþ from amino acids and

salvage synthesis of NADþ was worked out. NA and Nam were

collectively termed ‘niacins’. The broad use of niacin supple-

mentation has virtually eliminated pellagra.

NADþ is so termed because it consists of a Nam nucleotide,

that is, nicotinamide riboside 50-monophosphate, joined to

the phosphate of an adenine nucleotide, that is., adenosine

50-monophosphate. NADPþ is formed when a phosphate group

is added to the 20 position of adenosine (Figure 1). The glyco-

sidic linkages between bases and ribosyl moieties are b in both

nucleotides. The hydride-accepting moiety is the Nam base such

that the plus signs on NADþ and NADPþ refer to the oxidized,

hydride-accepting forms. The overall charge of these molecules

is negative because of the phosphates.

Salvage and De Novo Pathways

All dividing cells either form NADþ de novo from an ami-

no acid and/or resynthesize NADþ from NA, Nam, and/or

nicotinamide riboside (NR). These water-soluble vitamins are

NADþ breakdown products and metabolites that are trans-

ported systemically; these are available in the diet (Figure 2(a)).

NA is utilized by the Preiss–Handler pathway, which

involves three enzymatic steps through nicotinic acid mono-

nucleotide (NaMN) and nicotinic acid adenine dinucleotide

(NaAD). In vertebrates, Nam is utilized in two enzymatic

steps through nicotinamide mononucleotide (NMN). Since

Nam can be converted into NA in many bacteria by a nicoti-

namidase not encoded in vertebrate genomes, Nam entry

into the Preiss–Handler pathway in vertebrates is thought

to depend on bacterial nicotinamidase in the gut. NR can be

converted into two steps to NADþ through NMN, or can be

converted into NADþ via splitting the nucleoside followed by

Nam salvage. Specific transporters have been identified for

the uptake of NA and NR, but not Nam or nicotinic acid

riboside (NAR), an NADþ metabolite that can also be utilized

by yeast at high doses.

Most organisms synthesize NADþ from either tryptophan

or aspartic acid. De novo synthesis nearly always proceeds

through quinolinic acid (QA) and NaMN, at which point

NADþ is produced by the last two enzymes of the Preiss–

Handler pathway (Figure 3).

The phosphorylated forms of NADþ are also generated by

specific enzyme activities (Figure 2(b)). NADPþ is generated

from NADþ by NADþ kinase (NADK). In yeast, a mitochon-

drial NADH kinase generates NADPH from NADH. In addi-

tion, in bacteria and in animal mitochondria, the proton

translocating, membrane-bound NADPH transhydrogenase

interconverts NADPH and NADþ into NADPþ and NADH.

Thus, NADK activity is a gatekeeper of both phosphorylated

forms of NADþ, and NADPH transhydrogenase allows a cell to

maintain a redox balance in which NADþ levels exceed NADH

levels, while NADPH levels exceed those of NADPþ.

NADþ and NADPþ in Redox Metabolism

Electron transfers that occur in oxidation–reduction (redox)

reactions are essential to metabolism and life in all organisms.

Redox reactions are catalyzed by a large family of enzymes

called ‘oxidoreductases’. The electron-donating species in a

redox reaction is referred to as the reducing agent, or reductant,

and the electron-accepting species is the oxidizing agent, or

istry, (2013), vol. 1, pp. 172-178

NH2

NH2N

N NO

O OP

O

O-

OP

XO

X = H NAD+

X = PO3

OH

NNicotinamide

b-NAD+

Oxidized formb-NADH

Reduced form

O

O H H

N

ADPriboseADPribose

ADP NR

:H-

HO OH

O

O-

N+ NH2

O

AMP NMN

2-NADP+

Figure 1 NADþ/NADH and NADPþ/NADPH structure. NADþ is a dinucleotide consisting of a nicotinamide nucleotide, that is, nicotinamide riboside50-monophosphate (NMN) joined to the phosphate of an adenine nucleotide, that is, adenosine 50-monophosphate (AMP). In NADþ, the X in the20 position of the adenosine is an H, whereas in NADPþ, a phosphate group is in the X position. The glycosidic linkages between bases and ribosylmoieties are b in both nucleotides. The Nam base is the hydride-accepting moiety, such that the plus signs on NADþ and NADPþ refer to theoxidized, hydride-accepting forms.

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


oxidant. In biological redox reactions, the movement of elec-

trons often occurs concomitant with the loss of hydrogen. This

species is referred to as a hydride ion (:H–).

In NADþ-dependent dehydrogenation reactions, NADþ

and NADPþ undergo reduction of the nicotinamide ring to

form NADH and NADPH, respectively (Figure 1). In such

reactions, a hydride ion is transferred to the carbon at the

fourth position of the nicotinamide ring of NADþ (Figure 1).

This transfer of hydride can happen in two ways. In A-type

oxidoreductases, the hydrogen is transferred from above the

plane of the nicotinamide ring to the front of the nicotinamide

ring (A side), while B-type oxidoreductases transfer of the atom

occurs from below to the backside of the nicotinamide ring

(B side). This depends on how NADþ is oriented within the

nucleotide-binding domain of the enzyme.

Oxidoreductases bind the NAD(P)þ dinucleotide in a struc-

tural motif termed as a Rossmann fold (Figure 4(a)). The core

Rossman fold consists of one nucleotide-binding domain

constructed from at least three b-strands flanked by two a-helices (babab), though some oxidoreductases have addi-

tional b-strands. There are four important motifs found

within the Rossmann fold: a conserved positively charged

residue (Arg or Lys) at the beginning of the first b-strand, aconserved negatively charged residue (Glu or Asp) at the

end of the second b-strand, a phosphate-binding sequence –

GXGXXG– and six conserved positions occupied by small

hydrophobic amino acids.

Three of four conserved motifs within the Rossmann fold

have well-defined nucleotide-binding, structural, or catalytic

functions. The conserved positively charged residue (Arg or

Lys) found at the beginning of the first b-strand is not well

understood. It is thought to participate in stabilizing interac-

tions with nearby b-strands, though these are not fully char-

acterized. The conserved negatively charged residue at the

carboxyl terminus of the second b-strand is used to bind the

Encyclopedia of Biological Che

20-hydroxyl group of the adenine nucleotide. This site also

helps to distinguish enzymes that bind NADþ from those

that bind NADPþ, as this residue is uncharged in enzymes

that bind NADPþ in order to accommodate the 20-phosphatethat takes the place of the hydroxyl. In NADPþ-bindingenzymes, the phosphate interacts with a nearby arginine resi-

due instead. The phosphate-binding glycine-rich sequence

(GXGXXG) resides in a loop between the first a-helix and

b-strand. The first and second glycines are thought to allow

important turns of the main chain in this loop. These turns

promote an interaction between the main chain and the

diphosphate bridge of NADþ to occur (Figure 4(b)). The

third glycine promotes tight packing in the nucleotide-binding

domain that prohibits NADPþ from binding. NADPþ-bindingenzymes have a larger amino acid (alanine, serine, or proline)

in the place of the glycine, which disrupts the close packing

and allows NADPþ to bind. Finally, the hydrophobic core,

which contains six small hydrophobic amino acids, is neces-

sary for maintaining the proper packing of the b-strands withrespect to the a-helices. While these motifs form the proper

tertiary structure and interactions to specify binding of

NADþ versus NADPþ, some enzymes, such as aldose reductase,

glucose-6-phosphate dehydrogenase, and methylenetetrahy-

drofolate reductase, are exceptions to the rule, and bind both

NADþ and NADPþ.For the majority of enzymes that do show a high level of

specificity for either NADþ or NADPþ, the preference often

reflects the distinct metabolic role of the enzyme. NADþ is

typically utilized in catabolic pathways in which energy is

liberated from the oxidation of substrate molecules, whereas

NADPþ is most commonly utilized in anabolic reactions such

as fatty acid synthesis and photosynthesis. The ratios of oxi-

dized to reduced forms of NADþ and NADPþ reflect these

activities as well. Inmost tissues, in which it has beenmeasured,

the ratio of NADþ to NADH is high, providing ample NADþ to

mistry, (2013), vol. 1, pp. 172-178

(b)

NADKEC 2.7.1.23

Oxidoreductase

NAD+ NADP+

N

N+

N+

O-

O

COOH

QPRTEC 2.4.2.19

NaMNATEC 2.7.7.18

Pribo

COOH

(a)

QA NaMN

PNPEC 2.4.2.1

O-

O

Ribo

NAR

N

Import

O-

ONA

N

NH2

ONam NR

N+

O-

O

NADSEC 6.3.5.1

ADPribo

Bacterial/fungalnicotinamidase

EC 3.5.1.19

NaAD

N+

NH2

O

NMNATEC 2.7.7.1 5�-Nucleotidase

EC 3.1.3.55�-Nucleotidase

EC 3.1.3.5 NRKEC 2.7.1.22 NAPRT

EC 2.7.1.22 NamPRTEC 2.4.2.12

NRKEC 2.7.1.22

NAD-consumingreactions

ADPribo

NaD+

PNPEC 2.4.2.1

URHEC 3.2.2.3

N+

NH2

O

Pribo

NMN

N+

NH2

O

Ribo

Import

NADHKEC 2.7.1.86

NADPH transhydrogenaseEC 1.6.1.2

NADH

NADP+

NADPH

NAD+

Oxidoreductase

Figure 2 NADþ and NADPþ generation. (a) Cells have evolved pathways to salvage the pyridine ring of NADþ 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 thePreiss–Handler pathway, which involves three enzymatic steps. First, NA is converted into nicotinic acid mononucleotide (NaMN) by the nicotinicacid phosphoribosyltransferase enzyme (NAPRT). NaMN is subsequently converted into nicotinic acid adenine dinucleotide (NaAD), also calleddesamido NADþ, 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). NamPRTcatalyzes the addition of a phosphoribose moiety onto Nam forming nicotinamide mononucleotide (NMN). NMN is then converted into NADþ bythe NMNAT enzymes. Nam utilization differs among species. In some bacteria and fungi, Nam is converted into NA by a nicotinamidase enzyme(dotted line), after which it is utilized through the Priess–Handler pathway to form NADþ. NR can be utilized through two distinct pathways. In anNrk-dependent pathway, it is phosphorylated by nicotinamide riboside kinases (NRKs) to form NMN, which is converted into NADþ by NMNATenzymes. Alternatively, NR is utilized by purine nucleoside phosphorylase (PNP), which converts NR into Nam. Specific transporters have beenidentified that are responsible for the uptake of NA and NR. Another NADþ precursor, that is not efficiently imported, but that can be producedintracellularly, is nicotinic acid riboside (NAR). NAR is phosphorylated by NRK to form NaMN, and is hydrolyzed to NA by PNP. Data in yeastSaccharomyces cerevisiae indicate that NR and NAR are generated by the activities of NMN/NaMN 50-nucleotidases. (b) NADPþ and NADPHare generated from NADþ and NADH by kinases (NADK and NADHK). NADPH transhydrogenase interconverts NADPH and NADþ into NADPþ

and NADH.

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


accept hydride ions from substrates, whereas the level of

NADPþ is often significantly lower than NADPH promoting

hydride transfer to substrate molecules fromNADPH, as occurs

in anabolic pathways. Likewise, the organelles in which these

cofactors are primarily used are also distinct and reflective of

their different activities. NADþ is most often utilized in the

mitochondria for oxidation of fuel molecules (pyruvate, fatty

Encyclopedia of Biological Chem

acids, and a-keto acids), while NADPH serves as a reductant for

fatty acid synthesis in the cytosol.

Hydride transfer from substrate to NADþ has three prere-

quisites. First, the substrate must have high electron density on

the carbon that donates the hydride. This is often ensured by

interactions of the substrate with active site residues in redox

enzymes. Similarly, the C4 carbon of the Nam ring of NADþ,

istry, (2013), vol. 1, pp. 172-178

3-Hydroxy-anthranilate3,4-dioxygenase

EC 1.13.11.6

IDOEC 1.13.11.42

TDOEC 1.13.11.11

L-Tryptophan

Quinolinate

L-Aspartate

L-Aspartateoxidase

EC 1.4.3.16

COOH

NH2

NH

L-Kynurenine

COOH

HN

(a)

(b)

(c)

CHO

C

O NH2

COOH

COOHN

Quinolinate

COOH

COOHN

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

COOH

NH2N

COOHC

O NH2

NH2

COOHC

O NH2

NH2

OH

ArylformamidaseEC 3.5.1.9

KynureninaseEC 3.7.1.3

Kynurenine3-monooxygenase

EC 3.5.1.9

H2NH2C

OC

CH COH

OH

O

Iminoaspartate

HNH2C

OC

C COH

OH

OQuinolinatesynthase

EC 2.5.1.72

N-Formyl-kynurenine

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) ortryptophan 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-hydroxyanthranilic acid. 3-Hydroxyanthranilate 3,4-dioxygenase (3HAO) then converts 3-hydroxyanthranilic acid into 2-amino-3-carboxy-muconatesemialdehyde, which is converted into quinolinic acid by spontaneous cyclization. (b) Present in most prokaryotic systems, the de novo pathway fromaspartic acid synthesizes QA in two enzymatic steps. Aspartate is converted into iminoaspartate by L-aspartate oxidase (AO), which is subsequentlyconverted into QA by quinolinate synthase (QS).



which accepts the hydride ion, must have sufficiently low elec-

tron density to accept the hydride ion. Finally, the Nam moiety

of NADþ must be positioned close enough to the hydride-

donating species on the substrate to accept it. This is accom-

plished by the specific binding of NADþ in the Rossmann fold.

For example, the active site of lactate dehydrogenase (LDH), an

A-type oxidoreductase, utilizes an active site residue, histidine-

195, as a general base. In catalysis, the histidine residue removes

a proton from the hydroxyl group of the alcohol substrate

promoting the hydride transfer from the hydroxyl group to the

C4 position of the Nam moiety (Figure 5). Importantly, these

mechanisms both avoid actual formation of the hydride ion,

which is highly reactive, and cannot exist in water.

NADþ as a Prosthetic Group for Enzymes

In contrast to the reversible binding behavior of NADþco-enzymes in redox reactions, these cofactors can also function

as tightly bound prosthetic groups. In such enzymes, NADþ

and NADPþ do not dissociate with the release of the product,


but stay tightly bound. Enzymes that catalyze reactions using a

prosthetic group often have higher turnover rates than

enzymes that allow the coenzyme to dissociate by virtue of

eliminating slow association and dissociation steps. In addi-

tion, enzymes that bind and sequester a cofactor in the active

redox state are rendered insensitive to regulation due to the

redox state of the cell. This is due to the enzyme’s ability

to return the bound coenzyme to its original active redox

state after catalysis so that it can perform subsequent reactions.

Enzymes accomplish this in several ways. First, the enzyme can

participate in alternating oxidation and reduction reactions

with different substrates. Alternatively, the bound coenzyme

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

redox state prior to product release. Finally, in some reactions,

the coenzyme can accept only a pair of electrons and not the

entire hydride ion. In this way, the bound coenzyme can

promote catalysis without full oxidation or reduction occur-

ring, eliminating the regeneration requirement. Enzymes that

bind NADþ and NADPþ as prosthetic groups are termed

mistry, (2013), vol. 1, pp. 172-178

O

Lactate

O–

O

NH

His 195

N

H

NH2

CH2

CH

O

+NADPribose

H

H3C

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

(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.



‘nicotinoproteins’, which belong to a superfamily of metallo

alcohol dehydrogenases.

Nonredox Roles

In addition to its coenzymatic functions, NADþ is a consumed

substrate of multiple families of enzymes (Figure 6). Generally

termed as glycohydrolases, these enzymes cleave the glycosidic

bond between the nicotinamide and adenosine diphosphate

(ADP)ribose moieties of NADþ.One class ofNADþ-consuming enzymes possesses ADPribose

transferase (ART) and poly(ADPribose) polymerase (PARP)


activities, which transfer and/or polymerize NADþ-derivedADPribose to target molecules. PARP activity, which is consid-

ered one of the major NADþ-consuming activities within the

cell, is upregulated in response to genome damage. Individual

members of the PARP family have been shown to mediate

diverse cellular responses including inflammation, intracellu-

lar trafficking, and cell death.

A second class of NADþ-consuming enzymes consists of

cyclic (ADPribosyl) synthases, which are largely extracellular

enzymes that consume NADþ to produce and hydrolyze cyclic-

ADPribose. These activities are particularly important for cal-

cium (Ca2þ) regulation within the cell, as cyclic-ADPribose is a

potent Ca2þ-mobilizing second messenger.

istry, (2013), vol. 1, pp. 172-178

NAD+

ADPribosyltransferase

ADPribosylatedproteins+Nam

Poly (ADPribosyl) atedproteins+Nam

Deacetylated proteins+Ac-ADPribose+Nam

cADPribose

Poly (ADPribose)polymerase ADPribosyl

cyclase

Sirtuins

Figure 6 Nonredox roles of NADþ. Enzymes that cleave the glycosidic bond between the nicotinamide and ADPribose moieties of NADþ are termedglycohydrolases. These include ADPribose transferase (ART) and poly(ADPribose) polymerase (PARP) activities, which attach NADþ-derivedADPribose to target molecules, and cyclic ADPribosyl synthases, which consume NADþ to produce and hydrolyze cyclic-ADPribose. In addition,sirtuins catalyze NADþ-dependent protein lysine deacetylation by conversion of a lysine-acetylated peptide to a deacetylated peptide with productionof 20-O-acetyl-ADPribose and Nam as products.



A third class of NADþ-consuming enzymes is sirtuins, the

NADþ-dependent protein lysine deacetylases related to yeast

Sir2. These enzymes convert a lysine-acetylated peptide into a

deacetylated peptide with the production of 20-O-acetyl-ADPri-

bose and Nam as products. This process has been implicated in

gene regulation, enzyme activity, and longevity.

NADþ Alterations in Aging

Calorie restriction (CR) is a powerful means to extend life span

in model organisms. In yeast, Sir2 plays a role in mediating the

effect of CR on extension of life span. SinceNADþ is involved in

glucose utilization and is an essential Sir2 substrate, its metab-

olism is one potential subsystem that may be altered by CR.

Among the proposed mechanisms, it is conceivable that the

NADþ/NADH ratio, the NADþ/Nam ratio, altered flux, and/or

increased net synthesis may regulate sirtuin activities.

PARP activities may also influence the aging process in an

NADþ-dependent manner. In particular, the DNA-damage sur-

veillance activity of PARP has been proposed as a critical factor

to reduce genotoxic stress, maintain genomic stability, and

promote cellular survival. PARP family enzymes, tankyrase-1

and tankyrase-2, are also involved in the maintenance of telo-

mere length, which has been implicated in the regulation of

aging. Roles in aging and telomere maintenance are under-

scored by the observation that PARP-1, tankyrase-1, and

tankyrase-2 interact with the Werner syndrome protein,

which is altered in progeric humans.

Human Health and Disease

Widespread use of niacins has largely eliminated pellagra,

whereas high-dose NA is widely used for dyslipidemia and

high-dose Nam has been tested for efficacy in stroke and

other conditions. Since high-dose NA causes a flushing response

and high-dose Nam may inhibit sirtuins and other NADþ-consuming enzymes, NR is being tested for effectiveness in the


therapy of neurodegenerative diseases, such as Alzheimer’s and

Parkinson’s disease.

Many of the enzymes that use NADþ either as a co-enzyme

or as a substrate are considered as potential targets for drug

design. Although redox enzymes bind NADþ in a conserved

binding pocket, enzyme-specific inhibitors based on the struc-

ture of NADþ have been developed. For example, the nucleo-

side analog tiazofurin, which is converted in the cell into a

toxic analog of NADþ, tiazofurin adenine dinucleotide, is a

potent prodrug inhibitor of IMP dehydrogenase (IMPDH), an

enzyme important in de novo purine synthesis that might be

targeted in malignancies, viral infection, and/or for the pur-

poses of immunosuppression.

NADþ biosynthetic pathways have also been targeted, espe-

cially for antibiotic development. The differences in NADþ

biosynthetic pathways and enzymes between humans and

lower organisms make the development of specific inhibitors

to block NADþ synthesis in infectious organisms a plausible

path to antibiotics. So far, drugs of this nature have been used

to targetMycobacterium tuberculosis, the tuberculosis-causing bac-

terium. Isonicotinylhydrazine is a Nam-related anti-tuberculosis

agent that is metabolized to form inhibitors of redox enzymes. It

is anticipated that additional agents will be developed against

genetically validated enzymes, potentially using structure-based

drug design and/or high-throughput screening.

See also: Bioenergetics: Bioenergetics: General Definition ofPrinciples; Calcium Signaling by Cyclic ADP-Ribose and NAADP;Nicotinamide Nucleotide Transhydrogenase.

Further Reading

Bellamacina CR (1996) The nicotinamide dinucleotide binding motif: A comparison ofnucleotide binding proteins. FASEB Journal 10: 1257–1269.

Bogan KL and Brenner C (2008) Nicotinic acid, nicotinamide and nicotinamide riboside:A molecular evaluation of NADþ precursor vitamins in human nutrition. AnnualReview of Nutrition 28: 115–130.

Bogan KL, Evans C, Belenky P, et al. (2009) Identification of Isn1 and Sdt1 asglucose- and vitamin-regulated nicotinamide mononucleotide and nicotinic acidadenine mononucleotide 5’-nucleotidases responsible for production of

mistry, (2013), vol. 1, pp. 172-178



nicotinamide riboside and nicotinic acid riboside. Journal of Biological Chemistry284: 34861–34869.

Gazzaniga F, Stebbins R, Chang SZ, McPeek MA, and Brenner C (2009) Microbial NADmetabolism: Lessons from comparative genomics. Microbiology and MolecularBiology Reviews 73: 529–541.

Longo VD (2009) Linking sirtuins, IGF-I signaling and starvation. ExperimentalGerontology 44: 70–74.

Magni G, Amici A, Emanuelli M, et al. (2004) Enzymology of NADþ homeostasis inman. Cellular and Molecular Life Sciences 61: 19–34.


Nelson DL and Cox MM (2008) Biological oxidation–reduction reactions. In: LehningerPrinciples of Biochemistry, 5th edn., chapter 13, pp. 512–526. New York, NY:WH Freeman.

Oppenheimer NJ (2010) NADþ and NADPþ as prosthetic groups for enzymes.In: Encyclopedia of Life Sciences, doi:10.1002/9780470015902.a000637.pub2.Chichester: Wiley.

Ziegler M (2001) New functions of a long-known molecule: Emerging roles ofNAD in cellular signaling. European Journal of Biochemistry267: 1550–1564.

istry, (2013), vol. 1, pp. 172-178

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