Nicotinamide adenine dinucleotide

Nicotinamide adenine dinucleotide, abbreviated NAD+ , is a coenzyme found in all

living cells. The compound is a dinucleotide, since it consists of two nucleotides
joined through their phosphate groups. One nucleotide contains an adenine base
and the other nicotinamide.

In metabolism, NAD+ is involved in redox reactions, carrying electrons from one

reaction to another. The coenzyme is, therefore, found in two forms in cells: NAD+
is an oxidizing agent it accepts electrons from other molecules and becomes
reduced. This reaction forms NADH, which can then be used as a reducing agent to
donate electrons. These electron transfer reactions are the main function of NAD+ .
However, it is also used in other cellular processes, the most notable one being a
substrate of enzymes that add or remove chemical groups from proteins, in
posttranslational modifications. Because of the importance of these functions, the
enzymes involved in NAD+ metabolism are targets for drug discovery.

In organisms, NAD+ can be synthesized from simple building-blocks (de novo) from
the amino acids tryptophan or aspartic acid. In an alternative fashion, more complex
components of the coenzymes are taken up from food as the vitamin called niacin.
Similar compounds are released by reactions that break down the structure of
NAD+ . These preformed components then pass through a salvage pathway that
recycles them back into the active form. Some NAD+ is also converted into
nicotinamide adenine dinucleotide phosphate (NADP+ ); the chemistry of this
related coenzyme is similar to that of NAD+ , but it has different roles in
metabolism.

[edit] Physical and chemical properties

Nicotinamide adenine dinucleotide, like all dinucleotides, consists of two nucleotides

joined by a pair of bridging phosphate groups. The nucleotides consist of ribose
rings, one with adenine attached to the first carbon atom (the 1' position) and the
other with nicotinamide at this position. The nicotinamide moiety can be attached in
two orientations to this anomeric carbon atom. Because of these two possible
structures, the compound exists as two diastereomers. It is the -nicotinamide
diastereomer of NAD+ that is found in organisms. These nucleotides are joined
together by a bridge of two phosphate groups through the 5' carbons.[1]
In metabolism, the compound accepts or donates electrons in redox reactions. [2]
Such reactions (summarized in formula below) involve the removal of two hydrogen
atoms from the reactant (R), in the form of a hydride ion (H ), and a proton (H+ ).
The proton is released into solution, while the reductant RH2 is oxidized and NAD+
reduced to NADH by transfer of the hydride to the nicotinamide ring.

RH2 + NAD+ NADH + H+ + R;

From the hydride electron pair, one electron is transferred to the positively charged
nitrogen of the nicotinamide ring of NAD+ , and the second hydrogen atom
transferred to the C4 carbon atom opposite this nitrogen. The midpoint potential of
the NAD+ /NADH redox pair is 0.32 volts, which makes NADH a strong reducing
agent.[3] The reaction is easily reversible, when NADH reduces another molecule
and is re-oxidized to NAD+ . This means the coenzyme can continuously cycle
between the NAD+ and NADH forms without being consumed.[1]

In appearance, all forms of this coenzyme are white amorphous powders that are
hygroscopic and highly water-soluble.[4] The solids are stable if stored dry and in
the dark. Solutions of NAD+ are colorless and stable for about a week at 4 C and
neutral pH, but decompose rapidly in acids or alkalis. Upon decomposition, they
form products that are enzyme inhibitors.[5]

Both NAD+ and NADH strongly absorb

ultraviolet light because of the adenine. For
example, peak absorption of NAD+ is at a
wavelength of 259 nanometers (nm), with an
extinction coefficient of 16,900 M 1cm1. NADH
also absorbs at higher wavelengths, with a second
peak in UV absorption at 339 nm with an
extinction coefficient of 6,220 M 1cm1.[6] This
difference in the ultraviolet absorption spectra between the oxidized and reduced
forms of the coenzymes at higher wavelengths makes it simple to measure the
conversion of one to another in enzyme assays by measuring the amount of UV
absorption at 340 nm using a spectrophotometer.[6]

NAD+ and NADH also differ in their fluorescence. NADH in solution has an
emission peak at 460 nm and a fluorescence lifetime of 0.4 nanoseconds, while the
oxidized form of the coenzyme does not fluoresce. [7] The properties of the
fluorescence signal changes when NADH binds to proteins, so these changes can be
used to measure dissociation constants, which are useful in the study of enzyme
kinetics.[7][8] These changes in fluorescence are also used to measure changes in the
redox state of living cells, through fluorescence microscopy.[9]

[edit] Concentration and state in cells

In rat liver, the total amount of NAD+ and NADH is approximately 1 mole per
gram of wet weight, about 10 times the concentration of NADP+ and NADPH in the
same cells. [10] The actual concentration of NAD+ in cell cytosol is harder to
measure, with recent estimates in animal cells, ranging around 0.3 mM,[11][12] and
approximately 1.0 to 2.0 mM in yeast.[2] However, more than 80% of mitochondrial
NADH is bound to proteins, so the concentration in solution is much lower. [13]

Data for other compartments in the cell are limited, although, in the mitochondrion
the concentration of NAD+ is similar to that in the cytosol.[12] This NAD+ is carried
into the mitochondrion by a specific membrane transport protein, since the
coenzyme cannot diffuse across membranes.[14]

The balance between the oxidized and reduced forms of nicotinamide adenine
dinucleotide is called the NAD+ /NADH ratio. This ratio is an important component
of what is called the redox state of a cell, a measurement that reflects both the
metabolic activities and the health of cells. [15] The effects of the NAD+ /NADH ratio
are complex, controlling the activity of several key enzymes, including
glyceraldehyde 3-phosphate dehydrogenase and pyruvate dehydrogenase. In
healthy mammalian tissues, estimates of the ratio between free NAD+ and NADH
in the cytoplasm typically lie around 700; the ratio is thus favourable for oxidative
reactions. [16][17] The ratio of total NAD+ /NADH is much lower, with estimates
ranging from 0.05 to 4.[18] In contrast, the NADP+ /NADPH ratio is normally about
0.005, so NADPH is the dominant form of this coenzyme.[19] These different ratios
are key to the different metabolic roles of NADH and NADPH.

[edit] Biosynthesis

NAD+ is synthesized through two metabolic pathways. It is produced either in a de

novo pathway from amino acids or in salvage pathways by recycling preformed
components such as nicotinamide back to NAD+ .

[edit] De novo production

Most organisms synthesize NAD+

from simple components.[2] The
specific set of reactions differs among
organisms, but a common feature is
the generation of quinolinic acid (QA)
from an amino acideither
tryptophan (Trp) in animals and some
bacteria, or aspartic acid in some bacteria and plants.[20][21] The quinolinic acid is
converted to nicotinic acid mononucleotide (NaMN) by transfer of a phosphoribose
moiety. An adenylate moiety is then transferred to form nicotinic acid adenine
dinucleotide (NaAD). Finally, the nicotinic acid moiety in NaAD is amidated to a
nicotinamide (Nam) moiety, forming nicotinamide adenine dinucleotide. [2]

In a further step, some NAD+ is converted into NADP+ by NAD+ kinase, which
phosphorylates NAD+ .[22] In most organisms, this enzyme uses ATP as the source
of the phosphate group, although several bacteria such as Mycobacterium tuberculosis
and a hyperthermophilic archaeon Pyrococcus horikoshii, use inorganic
polyphosphate as an alternative phosphoryl donor.[23][24]

[edit] Salvage pathways

Besides assembling NAD+ de novo from simple amino acid precursors, cells also
salvage preformed compounds containing nicotinamide. Although other precursors
are known, the three natural compounds containing the nicotinamide ring and used
in these salvage metabolic pathways are nicotinic acid (Na), nicotinamide (Nam)
and nicotinamide riboside (NR).[2] These compounds can be taken up from the diet,
where the mixture of nicotinic acid and nicotinamide are called vitamin B3 or niacin.
However, these compounds are also produced within cells, when the nicotinamide
moiety is released from NAD+ in ADP-ribose transfer reactions. Indeed, the
enzymes involved in these salvage pathways appear to be concentrated in the cell
nucleus, which may compensate for the high level of reactions that consume NAD+
in this organelle.[25] Cells can also take up extracellular NAD+ from their
surroundings.[26]
Despite the presence of the de novo pathway, the salvage reactions are essential in
humans; a lack of niacin in the diet causes the vitamin deficiency disease
pellagra.[27] This high requirement for NAD+ results from the constant consumption
of the coenzyme in reactions such as posttranslational modifications, since the
cycling of NAD+ between oxidized and reduced forms in redox reactions does not
change the overall levels of the coenzyme.[2]

The salvage pathways used in microorganisms differ from those of mammals.[28]

Some pathogens, such as the yeast Candida glabrata and the bacterium Haemophilus
influenzae are NAD+ auxotrophs they cannot synthesize NAD+ but possess
salvage pathways and thus are dependent on external sources of NAD+ or its
precursors. [29][30] Even more surprising is the intracellular pathogen Chlamydia
trachomatis, which lacks recognizable candidates for any genes involved in the
biosynthesis or salvage of both NAD+ and NADP+ , and must acquire these
coenzymes from its host.[31]

[edit] Functions

Nicotinamide adenine dinucleotide has several

essential roles in metabolism. It acts as a
coenzyme in redox reactions, as a donor of ADP-
ribose moieties in ADP-ribosylation reactions, as a
precursor of the second messenger molecule cyclic
ADP-ribose, as well as acting as a substrate for
bacterial DNA ligases and a group of enzymes
called sirtuins that use NAD+ to remove acetyl
groups from proteins. In addition to these
metabolic functions, NAD+ emerges as an adenine
nucleotide that can be released from cells
spontaneously and by regulated mechanisms[33]
[34], and can therefore have important extracellular roles.[34]

[edit] Oxidoreductase Binding

The main role of NAD+ in metabolism is the transfer of electrons from one molecule
to another. Reactions of this type are catalyzed by a large group of enzymes called
oxidoreductases. The correct names for these enzymes contain the names of both
their substrates: for example NADH-ubiquinone oxidoreductase catalyzes the
oxidation of NADH by coenzyme Q.[35] However, these enzymes are also referred
to as dehydrogenases or reductases, with NADH-ubiquinone oxidoreductase
commonly being called NADH dehydrogenase or sometimes coenzyme Q reductase.[36]

When bound to a protein, NAD+ and NADH are usually held within a structural
motif known as the Rossmann fold.[37] The motif is named after Michael Rossmann
who was the first scientist to notice how common this structure is within nucleotide-
binding proteins. [38] This fold contains three or more parallel beta strands linked by
two alpha helices in the order beta-alpha-beta-alpha-beta. This forms a beta sheet
flanked by a layer of alpha helices on each side. Because each Rossmann fold binds
one nucleotide, binding domains for the dinucleotide NAD+ consist of two paired
Rossmann folds, with each fold binding one nucleotide within the cofactor. [38]
However, this fold is not universal among NAD-dependent enzymes, since a class
of bacterial enzymes involved in amino acid metabolism have recently been
discovered that bind the coenzyme, but lack this motif. [39]

When bound in the active site of an oxidoreductase, the nicotinamide ring of the
coenzyme is positioned so that it can accept a hydride from the other substrate.
Since the C4 carbon that accepts the hydrogen is prochiral, this can be exploited in
enzyme kinetics to give information about the enzyme's mechanism. This is done by
mixing an enzyme with a substrate that has deuterium atoms substituted for the
hydrogens, so the enzyme will reduce NAD+ by transferring deuterium rather than
hydrogen. In this case, an enzyme can produce one of two stereoisomers of NADH.
In some enzymes the hydrogen is transferred from above the plane of the
nicotinamide ring; these are called class A oxidoreductases, whereas class B enzymes
transfer the atom from below. [40]

Despite the similarity in how proteins bind the two coenzymes, enzymes almost
always show a high level of specificity for either NAD+ or NADP+ .[41] This
specificity reflects the distinct metabolic roles of the respective coenzymes, and is
the result of distinct sets of amino acid residues in the two types of coenzyme-
binding pocket. For instance, in the active site of NADP-dependent enzymes, an
ionic bond is formed between a basic amino acid side-chain and the acidic
phosphate group of NADP+ . On the converse, in NAD-dependent enzymes the
charge in this pocket is reversed, preventing NADP+ from binding. However, there
are a few exceptions to this general rule, and enzymes such as aldose reductase,
glucose-6-phosphate dehydrogenase, and methylenetetrahydrofolate reductase can
use both coenzymes in some species. [42]
[edit] Role in redox metabolism

The redox reactions catalyzed by oxidoreductases

are vital in all parts of metabolism, but one
particularly important area where these reactions
occur is in the release of energy from nutrients.
Here, reduced compounds such as glucose and
fatty acids are oxidized, thereby releasing energy.
This energy is transferred to NAD+ by reduction
to NADH, as part of beta oxidation, glycolysis,
and the citric acid cycle. In eukaryotes the
electrons carried by the NADH that is produced in
the cytoplasm are transferred into the mitochondrion (to reduce mitochondrial
NAD+ ) by mitochondrial shuttles, such as the malate-aspartate shuttle.[43] The
mitochondrial NADH is then oxidized in turn by the electron transport chain, which
pumps protons across a membrane and generates ATP through oxidative
phosphorylation.[44] These shuttle systems also have the same transport function in
chloroplasts.[45]

Since both the oxidized and reduced forms of nicotinamide adenine dinucleotide are
used in these linked sets of reactions, the cell maintains significant concentrations of
both NAD+ and NADH, with the high NAD+ /NADH ratio allowing this coenzyme
to act as both an oxidizing and a reducing agent.[46] In contrast, the main function
of NADPH is as a reducing agent in anabolism, with this coenzyme being involved
in pathways such as fatty acid synthesis and photosynthesis. Since NADPH is
needed to drive redox reactions as a strong reducing agent, the NADP+ /NADPH
ratio is kept very low.[46]

Although it is important in catabolism, NADH is also used in anabolic reactions,

such as gluconeogenesis.[47] This need for NADH in anabolism poses a problem for
prokaryotes growing on nutrients that release only a small amount of energy. For
example, nitrifying bacteria such as Nitrobacter oxidize nitrite to nitrate, which
releases sufficient energy to pump protons and generate ATP, but not enough to
produce NADH directly.[48] As NADH is still needed for anabolic reactions, these
bacteria use a nitrite oxidoreductase to produce enough proton-motive force to run
part of the electron transport chain in reverse, generating NADH. [49]
[edit] Non-redox roles

The coenzyme NAD+ is also consumed in ADP-ribose transfer reactions. For

example, enzymes called ADP-ribosyltransferases add the ADP-ribose moiety of this
molecule to proteins, in a posttranslational modification called ADP-ribosylation.[50]
NAD+ may also be added onto cellular RNA as a base modification. [51] ADP-
ribosylation involves either the addition of a single ADP-ribose moiety, in mono-
ADP-ribosylation, or the transferral of ADP-ribose to proteins in long branched
chains, which is called poly(ADP-ribosyl)ation.[52] Mono-ADP-ribosylation was first
identified as the mechanism of a group of bacterial toxins, notably cholera toxin, but
it is also involved in normal cell signaling.[53][54] Poly(ADP-ribosyl)ation is carried
out by the poly(ADP-ribose) polymerases.[52][55] The poly(ADP-ribose) structure is
involved in the regulation of several cellular events and is most important in the cell
nucleus, in processes such as DNA repair and telomere maintenance. [55] In addition
to these functions within the cell, a group of extracellular ADP-ribosyltransferases
has recently been discovered, but their functions remain obscure.[56]

Another function of this coenzyme in cell

signaling is as a precursor of cyclic ADP-
ribose, which is produced from NAD+ by
ADP-ribosyl cyclases, as part of a second
messenger system.[57] This molecule acts in
calcium signaling by releasing calcium from
intracellular stores. [58] It does this by binding
to and opening a class of calcium channels called ryanodine receptors, which are
located in the membranes of organelles, such as the endoplasmic reticulum.[59]

NAD+ is also consumed by sirtuins, which are NAD-dependent deacetylases, such

as Sir2.[60] These enzymes act by transferring an acetyl group from their substrate
protein to the ADP-ribose moiety of NAD+ ; this cleaves the coenzyme and releases
nicotinamide and O-acetyl-ADP-ribose. The sirtuins mainly seem to be involved in
regulating transcription through deacetylating histones and altering nucleosome
structure. [61] However, non-histone proteins can be deacetylated by sirtuins as well.
These activities of sirtuins are particularly interesting because of their importance in
the regulation of aging.[62]

Other NAD-dependent enzymes include bacterial DNA ligases, which join two
DNA ends by using NAD+ as a substrate to donate an adenosine monophosphate
(AMP) moiety to the 5' phosphate of one DNA end. This intermediate is then
attacked by the 3' hydroxyl group of the other DNA end, forming a new
phosphodiester bond.[63] This contrasts with eukaryotic DNA ligases, which use
ATP to form the DNA-AMP intermediate. [64]

[edit] Extracellular actions of NAD+

In recent years, NAD+ has also been recognized as an extracellular signaling

molecule involved in cell-to-cell communication. [34][65][66] NAD+ is released from
neurons in blood vessels[33], urinary bladder[33][67], large intestine [68][69], from
neurosecretory cells[70], and from brain synaptosomes [71], and is proposed to be a
novel neurotransmitter that transmits information from nerves to effector cells in
smooth muscle organs.[68][69] Further studies are needed to determine the
underlying mechanisms of its extracellular actions and their importance for human
health and diseases.

[edit] Pharmacology and medical uses

The enzymes that make and use NAD+ and NADH are important in both current
pharmacology and the research into future treatments for disease. [72] Drug design
and drug development exploits NAD+ in three ways: as a direct target of drugs, by
designing enzyme inhibitors or activators based on its structure that change the
activity of NAD-dependent enzymes, and by trying to inhibit NAD+
biosynthesis. [73]

The coenzyme NAD+ is not itself currently used as a treatment for any disease.
However, it is potentially useful in the therapy of neurodegenerative diseases such
as Alzheimer's and Parkinson disease.[2] Evidence on the use of NAD+ in
neurodegeneration is mixed; studies in mice are promising,[74] whereas a placebo-
controlled clinical trial failed to show any effect.[75] NAD+ is also a direct target of
the drug isoniazid, which is used in the treatment of tuberculosis, an infection
caused by Mycobacterium tuberculosis. Isoniazid is a prodrug and once it has entered
the bacteria, it is activated by a peroxidase, which oxidizes the compound into a free
radical form. [76] This radical then reacts with NADH, to produce adducts that are
very potent inhibitors of the enzymes enoyl-acyl carrier protein reductase,[77] and
dihydrofolate reductase.[78]
Since a large number of oxidoreductases use NAD+ and NADH as substrates, and
bind them using a highly conserved structural motif, the idea that inhibitors based
on NAD+ could be specific to one enzyme is surprising.[79] However, this can be
possible: for example, inhibitors based on the compounds mycophenolic acid and
tiazofurin inhibit IMP dehydrogenase at the NAD+ binding site. Because of the
importance of this enzyme in purine metabolism, these compounds may be useful
as anti-cancer, anti-viral, or immunosuppressive drugs.[79][80] Other drugs are not
enzyme inhibitors, but instead activate enzymes involved in NAD+ metabolism.
Sirtuins are a particularly interesting target for such drugs, since activation of these
NAD-dependent deacetylases extends lifespan.[81] Compounds such as resveratrol
increase the activity of these enzymes, which may be important in their ability to
delay aging in both vertebrate, [82] and invertebrate model organisms.[83][84]

Because of the differences in the metabolic pathways of NAD+ biosynthesis between

organisms, such as between bacteria and humans, this area of metabolism is a
promising area for the development of new antibiotics.[85][86] For example, the
enzyme nicotinamidase, which converts nicotinamide to nicotinic acid, is a target for
drug design, as this enzyme is absent in humans but present in yeast and
bacteria. [28]

[edit] History

The coenzyme NAD+ was first discovered by the British

biochemists Arthur Harden and William Youndin in
1906.[87] They noticed that adding boiled and filtered
yeast extract greatly accelerated alcoholic fermentation in
unboiled yeast extracts. They called the unidentified
factor responsible for this effect a coferment. Through a
long and difficult purification from yeast extracts, this
heat-stable factor was identified as a nucleotide sugar
phosphate by Hans von Euler-Chelpin.[88] In 1936, the
German scientist Otto Heinrich Warburg showed the
function of the nucleotide coenzyme in hydride transfer
and identified the nicotinamide portion as the site of
redox reactions. [89]

A source of nicotinamide was identified in 1938, when Conrad Elvehjem purified

niacin from liver and showed this vitamin contained nicotinic acid and
nicotinamide. [90] Then, in 1939, he provided the first strong evidence that niacin was
used to synthesize NAD+ .[91] In the early 1940s, Arthur Kornberg made another
important contribution towards understanding NAD+ metabolism, by being the first
to detect an enzyme in the biosynthetic pathway.[92] Subsequently, in 1949, the
American biochemists Morris Friedkin and Albert L. Lehninger proved that NADH
linked metabolic pathways such as the citric acid cycle with the synthesis of ATP in
oxidative phosphorylation. [93] Finally, in 1959, Jack Preiss and Philip Handler
discovered the intermediates and enzymes involved in the biosynthesis of
NAD+ ;[94][95] consequently, de novo synthesis is often called the Preiss-Handler
pathway in their honor.

The non-redox roles of NAD(P) are a recent discovery. [1] The first of these functions
to be identified was the use of NAD+ as the ADP-ribose donor in ADP-ribosylation
reactions, observed in the early 1960s. [96] Later studies in the 1980s and 1990s
revealed the activities of NAD+ and NADP+ metabolites in cell signaling such as
the action of cyclic ADP-ribose, which was discovered in 1987.[97] The metabolism
of NAD+ has remained an area of intense research into the 21st century, with
interest being heightened after the discovery of the NAD+ -dependent protein
deacetylases called sirtuins in 2000, by Shinichiro Imai and coworkers at the
Massachusetts Institute of Technology.[98]

[edit] See also

List of oxidoreductases
Enzyme catalysis

[edit] References

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[edit] Further reading

Function

Nelson DL; Cox MM (2004). Lehninger Principles of Biochemistry (4th ed.). W. H.

Freeman. ISBN 0-7167-4339-6.
Bugg, T (2004). Introduction to Enzyme and Coenzyme Chemistry (2nd ed.).
Blackwell Publishing Limited. ISBN 1-4051-1452-5.
Lee HC (2002). Cyclic ADP-Ribose and NAADP: Structure, Metabolism and
Functions. Kluwer Academic Publishers. ISBN 1-4020-7281-3.

History

Cornish-Bowden, Athel (1997). New Beer in an Old Bottle. Eduard Buchner and the
Growth of Biochemical Knowledge.. Valencia: Universitat de Valencia. ISBN 84-
370-3328-4., A history of early enzymology.
Williams, Henry Smith, 18631943 (1904). Modern Development of the Chemical
and Biological Sciences. A History of Science: in Five Volumes. IV. New York:
Harper and Brothers., A textbook from the 19th century.

[edit] External links

NAD bound to proteins in the PDB

NAD Animation (Flash Required)
-Nicotinamide adenine dinucleotide (NAD+ , oxidized) and NADH (reduced)
Chemical data sheet from Sigma-Aldrich
NAD+ , NADH and NAD synthesis pathway at the MetaCyc database
List of oxidoreductases at the SWISS-PROT database