Nicotinamide adenine dinucleotide

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide 

Nicotinamide adenine dinucleotide

Names
Other names Diphosphopyridine nucleotide (DPN+), Coenzyme I
Identifiers
CAS Number	53-84-9  53-59-8 (phosphate)  58-68-4 (NADH)
3D model (JSmol)	NAD+: Interactive image NADH: Interactive image
ChEBI	CHEBI:16908
ChEMBL	ChEMBL1628272
ChemSpider	5681
DrugBank	DB00157
ECHA InfoCard	100.000.169
IUPHAR/BPS	2451
KEGG	C00003
PubChem CID	925
RTECS number	UU3450000
UNII	0U46U6E8UK  BY8P107XEP (phosphate)  4J24DQ0916 (NADH)

InChI

SMILES
Properties
Chemical formula	C21H28N7O14P2
Molar mass	663.43 g/mol
Appearance	White powder
Melting point	160 °C (320 °F; 433 K)
Hazards
Occupational safety and health (OHS/OSH):
Main hazards	Not hazardous
NFPA 704 (fire diamond)	1 1 0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD⁺ and NADH (H for hydrogen), respectively.

In metabolism, nicotinamide adenine dinucleotide is involved in redox reactions, carrying electrons from one reaction to another. The cofactor is, therefore, found in two forms in cells: NAD⁺ is an oxidizing agent – it accepts electrons from other molecules and becomes reduced. This reaction, also with H⁺, 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, most notably as a substrate of enzymes in adding or removing chemical groups to or from, respectively, 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 either tryptophan or aspartic acid, each a case of an amino acid; alternatively, more complex components of the coenzymes are taken up from nutritive compounds such as niacin; similar compounds are produced by reactions that break down the structure of NAD, providing a salvage pathway that “recycles” them back into their respective active form.

Some NAD is converted into the coenzyme nicotinamide adenine dinucleotide phosphate (NADP); its chemistry largely parallels that of NAD, though predominantly its role is as a cofactor in anabolic metabolism.

The NAD⁺ chemical species’ superscripted addition sign reflects the formal charge on one of its nitrogen atoms; this species is actually a singly charged anion – carrying a (negative) ionic charge of 1 – under conditions of physiological pH.

Physical and chemical properties

Further information: Redox

Nicotinamide adenine dinucleotide consists of two nucleosides joined by pyrophosphate. The nucleosides each contain a ribose ring, one with adenine attached to the first carbon atom (the 1' position) (adenosine diphosphate ribose) and the other with nicotinamide at this position.^[3][4]

The redox reactions of nicotinamide adenine dinucleotide.

The compound accepts or donates the equivalent of H⁻. 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 atom of the nicotinamide ring of NAD⁺, and the second hydrogen atom transferred to the C4 carbon atom opposite this N atom. The midpoint potential of the NAD⁺/NADH redox pair is −0.32 volts, which makes NADH a moderately strong reducing agent. 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.

In appearance, all forms of this coenzyme are white amorphous powders that are hygroscopic and highly water-soluble. 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 acidic or alkaline solutions. Upon decomposition, they form products that are enzyme inhibitors.

UV absorption spectra of NAD⁺ and NADH.

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⁻¹cm⁻¹. NADH also absorbs at higher wavelengths, with a second peak in UV absorption at 339 nm with an extinction coefficient of 6,220 M⁻¹cm⁻¹. 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.

NAD⁺ and NADH also differ in their fluorescence. Freely diffusing NADH in aqueous solution, when excited at the nicotinamide absorbance of ~335 nm (near UV), fluoresces at 445–460 nm (violet to blue) with a fluorescence lifetime of 0.4 nanoseconds, while NAD⁺ does not fluoresce. 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. These changes in fluorescence are also used to measure changes in the redox state of living cells, through fluorescence microscopy.

Concentration and state in cells

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

NAD⁺ concentrations are highest in the mitochondria, constituting 40% to 70% of the total cellular NAD⁺. NAD⁺ in the cytosol is carried into the mitochondrion by a specific membrane transport protein, since the coenzyme cannot diffuse across membranes. The intracellular half-life of NAD⁺ was claimed to be between 1–2 hours by one review, whereas another review gave varying estimates based on compartment: intracellular 1–4 hours, cytoplasmic 2 hours, and mitochondrial 4–6 hours.

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. 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 of free NAD⁺ to NADH in the cytoplasm typically lie around 700:1; the ratio is thus favorable for oxidative reactions. The ratio of total NAD⁺/NADH is much lower, with estimates ranging from 3–10 in mammals. In contrast, the NADP⁺/NADPH ratio is normally about 0.005, so NADPH is the dominant form of this coenzyme. These different ratios are key to the different metabolic roles of NADH and NADPH.

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⁺. Although most tissues synthesize NAD⁺ by the salvage pathway in mammals, much more de novo synthesis occurs in the liver from tryptophan, and in the kidney and macrophages from nicotinic acid.

De novo production

Some metabolic pathways that synthesize and consume NAD⁺ in vertebrates.The abbreviations are defined in the text.

Most organisms synthesize NAD⁺ from simple components. The specific set of reactions differs among organisms, but a common feature is the generation of quinolinic acid (QA) from an amino acid – either tryptophan (Trp) in animals and some bacteria, or aspartic acid (Asp) in some bacteria and plants. 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.

In a further step, some NAD⁺ is converted into NADP⁺ by NAD⁺ kinase, which phosphorylates NAD⁺. 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.

Salvage pathways use three precursors for NAD⁺.

Salvage pathways

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. 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. The major source of NAD⁺ in mammals is the salvage pathway which recycles the nicotinamide produced by enzymes utilizing NAD⁺. The first step, and the rate-limiting enzyme in the salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT), which produces nicotinamide mononucleotide (NMN). NMN is the immediate precursor to NAD+ in the salvage pathway.

Besides assembling NAD⁺ de novo from simple amino acid precursors, cells also salvage preformed compounds containing a pyridine base. The three vitamin precursors used in these salvage metabolic pathways are nicotinic acid (NA), nicotinamide (Nam) and nicotinamide riboside (NR). These compounds can be taken up from the diet and are termed vitamin B₃ or niacin. However, these compounds are also produced within cells and by digestion of cellular NAD⁺. Some of 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. There are some reports that mammalian cells can take up extracellular NAD⁺ from their surroundings, and both nicotinamide and nicotinamide riboside can be absorbed from the gut.

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

Functions

Rossmann fold in part of the lactate dehydrogenase of Cryptosporidium parvum, showing NAD⁺ in red, beta sheets in yellow, and alpha helices in purple.

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, and can therefore have important extracellular roles.

Oxidoreductase binding of NAD

Further information: Protein structure and Oxidoreductase

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. 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.

There are many different superfamilies of enzymes that bind NAD⁺ / NADH. One of the most common superfamilies includes a structural motif known as the Rossmann fold. The motif is named after Michael Rossmann, who was the first scientist to notice how common this structure is within nucleotide-binding proteins.

An example of a NAD-binding bacterial enzyme involved in amino acid metabolism that does not have the Rossmann fold is found in Pseudomonas syringae pv. tomato (PDB: 2CWH​; InterPro: IPR003767).

In this diagram, the hydride acceptor C4 carbon is shown at the top. When the nicotinamide ring lies in the plane of the page with the carboxy-amide to the right, as shown, the hydride donor lies either "above" or "below" the plane of the page. If "above" hydride transfer is class A, if "below" hydride transfer is class B.

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. Depending on the enzyme, the hydride donor is positioned either "above" or "below" the plane of the planar C4 carbon, as defined in the figure. Class A oxidoreductases transfer the atom from above; class B enzymes transfer it from below. 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.

Despite the similarity in how proteins bind the two coenzymes, enzymes almost always show a high level of specificity for either NAD⁺ or NADP⁺. 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.

Role in redox metabolism

A simplified outline of redox metabolism, showing how NAD⁺ and NADH link the citric acid cycle and oxidative phosphorylation.

 

Further information: Cellular respiration and Oxidative phosphorylation

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. 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. These shuttle systems also have the same transport function in chloroplasts.

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. 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.

Although it is important in catabolism, NADH is also used in anabolic reactions, such as gluconeogenesis. 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. 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.

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. 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. 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. Poly(ADP-ribosyl)ation is carried out by the poly(ADP-ribose) polymerases. 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. In addition to these functions within the cell, a group of extracellular ADP-ribosyltransferases has recently been discovered, but their functions remain obscure. NAD⁺ may also be added onto cellular RNA as a 5'-terminal modification.

The structure of cyclic ADP-ribose.

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. This molecule acts in calcium signaling by releasing calcium from intracellular stores. 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, and inducing the activation of the transcription factor NAFC3

NAD⁺ is also consumed by different NAD+-consuming enzymes, such as CD38, CD157, PARPs and the NAD-dependent deacetylases (sirtuins,such as Sir2.). 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. 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.

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. This contrasts with eukaryotic DNA ligases, which use ATP to form the DNA-AMP intermediate.

Li et al. have found that NAD⁺ directly regulates protein-protein interactions. They also show that one of the causes of age-related decline in DNA repair may be increased binding of the protein DBC1 (Deleted in Breast Cancer 1) to PARP1 (poly[ADP–ribose] polymerase 1) as NAD⁺ levels decline during aging. Thus, the modulation of NAD⁺ may protect against cancer, radiation, and aging.

Extracellular actions of NAD⁺

In recent years, NAD⁺ has also been recognized as an extracellular signaling molecule involved in cell-to-cell communication. NAD⁺ is released from neurons in blood vessels, urinary bladder, large intestine, from neurosecretory cells, and from brain synaptosomes, and is proposed to be a novel neurotransmitter that transmits information from nerves to effector cells in smooth muscle organs. In plants, the extracellular nicotinamide adenine dinucleotide induces resistance to pathogen infection and the first extracellular NAD receptor has been identified. Further studies are needed to determine the underlying mechanisms of its extracellular actions and their importance for human health and life processes in other organisms.

Clinical significance

The enzymes that make and use NAD⁺ and NADH are important in both pharmacology and the research into future treatments for disease. 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.

Because cancer cells utilize increased glycolysis, and because NAD enhances glycolysis, nicotinamide phosphoribosyltransferase (NAD salvage pathway) is often amplified in cancer cells.

It has been studied for its potential use in the therapy of neurodegenerative diseases such as Alzheimer's and Parkinson's disease and Muliple sclerosis. A placebo-controlled clinical trial of NADH (which excluded NADH precursors) in people with Parkinson's failed to show any effect.

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 enzyme, which oxidizes the compound into a free radical form. This radical then reacts with NADH, to produce adducts that are very potent inhibitors of the enzymes enoyl-acyl carrier protein reductase, and dihydrofolate reductase.

Since many 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. 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. 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 in some animal models. Compounds such as resveratrol increase the activity of these enzymes, which may be important in their ability to delay aging in both vertebrate, and invertebrate model organisms. In one experiment, mice given NAD for one week had improved nuclear-mitochrondrial communication.

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. 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.

In bacteriology, NAD, sometimes referred to factor V, is used as a supplement to culture media for some fastidious bacteria.

History

Arthur Harden, co-discoverer of NAD

 

Further information: History of biochemistry

The coenzyme NAD⁺ was first discovered by the British biochemists Arthur Harden and William John Young in 1906. 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. 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.

Vitamin precursors of NAD⁺ were first identified in 1938, when Conrad Elvehjem showed that liver has an "anti-black tongue" activity in the form of nicotinamide. Then, in 1939, he provided the first strong evidence that niacin is used to synthesize NAD⁺. In the early 1940s, Arthur Kornberg was the first to detect an enzyme in the biosynthetic pathway. 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. In 1958, Jack Preiss and Philip Handler discovered the intermediates and enzymes involved in the biosynthesis of NAD⁺; salvage synthesis from nicotinic acid is termed the Preiss-Handler pathway. In 2004, Charles Brenner and co-workers uncovered the nicotinamide riboside kinase pathway to NAD⁺.

The non-redox roles of NAD(P) were discovered later. The first to be identified was the use of NAD⁺ as the ADP-ribose donor in ADP-ribosylation reactions, observed in the early 1960s. 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.

The metabolism of NAD⁺ remained an area of intense research into the 21st century, with interest heightened after the discovery of the NAD⁺-dependent protein deacetylases called sirtuins in 2000, by Shin-ichiro Imai and coworkers in the laboratory of Leonard P. Guarente. In 2009 Imai proposed the "NAD World" hypothesis that key regulators of aging and longevity in mammals are sirtuin 1 and the primary NAD⁺ synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). In 2016 Imai expanded his hypothesis to "NAD World 2.0", which postulates that extracellular NAMPT from adipose tissue maintains NAD⁺ in the hypothalamus (the control center) in conjunction with myokines from skeletal muscle cells.

Niacin

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Niacin 

Niacin

Names
Pronunciation	/ˈnaɪəsɪn/
Preferred IUPAC name Pyridine-3-carboxylic acid
Other names Nicotinic acid (INN) Bionic Vitamin B3 Vitamin PP
Identifiers
CAS Number	59-67-6
3D model (JSmol)	Interactive image
3DMet	B00073
Beilstein Reference	109591
ChEBI	CHEBI:15940
ChEMBL	ChEMBL573
ChemSpider	913
DrugBank	DB00627
ECHA InfoCard	100.000.401
EC Number	200-441-0
Gmelin Reference	3340
IUPHAR/BPS	1588
KEGG	D00049  C00253
MeSH	Niacin
PubChem CID	938
RTECS number	QT0525000
UNII	2679MF687A
CompTox Dashboard (EPA)	DTXSID1020932

InChI

SMILES
Properties
Chemical formula	C6H5NO2
Molar mass	123.111 g·mol−1
Appearance	White, translucent crystals
Density	1.473 g cm−3
Melting point	237 °C; 458 °F; 510 K
Solubility in water	18 g L−1
log P	0.219
Acidity (pKa)	2.0, 4.85
Isoelectric point	4.75
Refractive index (nD)	1.4936
Dipole moment	0.1271305813 D
Thermochemistry
Std enthalpy of formation (ΔfH⦵298)	−344.9 kJ mol−1
Std enthalpy of combustion (ΔcH⦵298)	−2.73083 MJ mol−1
Pharmacology
ATC code	C04AC01 (WHO) C10BA01 (WHO) C10AD02 (WHO) C10AD52 (WHO)
License data	EU EMA: by Nicotinic acid
Routes of administration	Intramuscular, by mouth
Pharmacokinetics:
Biological half-life	20–45 min
Hazards
GHS labelling:
Pictograms
Signal word	Warning
Hazard statements	H319
Precautionary statements	P264, P280, P305+P351+P338, P337+P313, P501
NFPA 704 (fire diamond)	1 1 0
Flash point	193 °C (379 °F; 466 K)
Autoignition temperature	365 °C (689 °F; 638 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Niacin
INN: Nicotinic acid

Clinical data
Trade names	Niacor, Niaspan, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682518
License data	EU EMA: by Nicotinic acid US DailyMed: Niacin
Pregnancy category	AU: Exempt
Legal status
Legal status	US: OTC / Rx-only
Identifiers
PDB ligand	NIO (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID1020932
ECHA InfoCard	100.000.401

Space-filling model of niacin

Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B₃, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variety of whole and processed foods, with highest contents in fortified packaged foods, meat, poultry, red fish such as tuna and salmon, lesser amounts in nuts, legumes and seeds. Niacin as a dietary supplement is used to treat pellagra, a disease caused by niacin deficiency. Signs and symptoms of pellagra include skin and mouth lesions, anemia, headaches, and tiredness. Many countries mandate its addition to wheat flour or other food grains, thereby reducing the risk of pellagra.

The amide derivative nicotinamide (niacinamide) is a component of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP+). Although niacin and nicotinamide are identical in their vitamin activity, nicotinamide does not have the same pharmacological, lipid-modifying effects or side effects as niacin, i.e., when niacin takes on the -amide group, it does not reduce cholesterol nor cause flushing. Nicotinamide is recommended as a treatment for niacin deficiency because it can be administered in remedial amounts without causing the flushing, considered an adverse effect.

Niacin is also a prescription medication. Amounts far in excess of the recommended dietary intake for vitamin functions will lower blood triglycerides and low density lipoprotein cholesterol (LDL-C), and raise blood high density lipoprotein cholesterol (HDL-C, often referred to as "good" cholesterol). There are two forms: immediate-release and sustained-release niacin. Initial prescription amounts are 500 mg/day, increased over time until a therapeutic effect is achieved. Immediate-release doses can be as high as 3,000 mg/day; sustained-release as high as 2,000 mg/day. Despite the proven lipid changes, niacin has not been found useful for decreasing the risk of cardiovascular disease in those already on a statin. A 2010 review had concluded that niacin was effective as a mono-therapy, but a 2017 review incorporating twice as many trials concluded that prescription niacin, while affecting lipid levels, did not reduce all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes. Prescription niacin was shown to cause hepatotoxicity and increase risk of type 2 diabetes. Niacin prescriptions in the U.S. had peaked in 2009, at 9.4 million, declining to 800 thousand by 2020.

Niacin has the formula C
₆H
₅NO
₂ and belongs to the group of the pyridinecarboxylic acids. As the precursor for nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, niacin is involved in DNA repair.

Definition

Niacin is both a vitamin, i.e., an essential nutrient, marketed as a dietary supplement, and in the US, a prescription medicine. As a vitamin, it is precursor of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These compounds are coenzymes for many dehydrogenases, participating in many hydrogen transfer processes. NAD is important in catabolism of fat, carbohydrate, protein, and alcohol, as well as cell signaling and DNA repair, and NADP mostly in anabolism reactions such as fatty acid and cholesterol synthesis. Vitamin intake recommendations made by several countries are that intakes of 14–18 mg/day are sufficient to meet the needs of healthy adults. Niacin or nicotinamide (niacinamide) are used for prevention and treatment of pellagra, a disease caused by lack of the vitamin. When niacin is used as a medicine to treat elevated cholesterol and triglycerides, daily doses range from 500 to 3,000 mg/day. High-dose nicotinamide does not have this medicinal effect.

Vitamin deficiency

Main article: Pellagra

 

A man with pellagra, which is caused by a chronic lack of vitamin B₃ in the diet

Severe deficiency of niacin in the diet causes the disease pellagra, characterized by diarrhea, sun-sensitive dermatitis involving hyperpigmentation and thickening of the skin (see image), inflammation of the mouth and tongue, delirium, dementia, and if left untreated, death. Common psychiatric symptoms include irritability, poor concentration, anxiety, fatigue, loss of memory, restlessness, apathy, and depression. The biochemical mechanism(s) for the observed deficiency-caused neurodegeneration are not well understood, but may rest on: A) the requirement for nicotinamide adenine dinucleotide (NAD+) to suppress the creation of neurotoxic tryptophan metabolites, B) inhibition of mitochondrial ATP generation, resulting in cell damage; C), activation of the poly (ADP-ribose) polymerase (PARP) pathway, as PARP is a nuclear enzyme involved in DNA repair, but in the absence of NAD+ can lead to cell death; D) reduced synthesis of neuro-protective brain-derived neurotrophic factor or its receptor tropomyosin receptor kinase B; or E) changes to genome expression directly due to the niacin deficiency.

Niacin deficiency is rarely seen in developed countries, and it is more typically associated with poverty, malnutrition or malnutrition secondary to chronic alcoholism. It also tends to occur in less developed areas where people eat maize (corn) as a staple food, as maize is the only grain low in digestible niacin. A cooking technique called nixtamalization i.e., pretreating with alkali ingredients, increases the bioavailability of niacin during maize meal/flour production. For this reason, people who consume corn as tortillas or hominy are at less risk of niacin deficiency.

For treating deficiency, the World Health Organization (WHO) recommends administering niacinamide i.e., nicotinamide, instead of niacin, to avoid the flushing side effect commonly caused by the latter. Guidelines suggest using 300 mg/day for three to four weeks. Dementia and dermatitis show improvement within a week. Because deficiencies of other B-vitamins may be present, the WHO recommends a multi-vitamin in addition to the niacinamide.

Hartnup disease is a hereditary nutritional disorder resulting in niacin deficiency. It is named after an English family with a genetic disorder that resulted in a failure to absorb the essential amino acid tryptophan, tryptophan being a precursor for niacin synthesis. The symptoms are similar to pellagra, including red, scaly rash and sensitivity to sunlight. Oral niacin or niacinamide is given as a treatment for this condition in doses ranging from 50 to 100 mg twice a day, with a good prognosis if identified and treated early. Niacin synthesis is also deficient in carcinoid syndrome, because of metabolic diversion of its precursor tryptophan to form serotonin.

Measuring vitamin status

Plasma concentrations of niacin and niacin metabolites are not useful markers of niacin status. Urinary excretion of the methylated metabolite N1-methyl-nicotinamide is considered reliable and sensitive. The measurement requires a 24-hour urine collection. For adults, a value of less than 5.8 μmol/day represent deficient niacin status and 5.8 to 17.5 μmol/day represents low. According to the World Health Organization, an alternative mean of expressing urinary N1-methyl-nicotinamide is as mg/g creatinine in a 24-hour urine collection, with deficient defined as <0.5, low 0.5-1.59, acceptable 1.6-4.29, and high >4.3 Niacin deficiency occurs before the signs and symptoms of pellagra appear. Erythrocyte nicotinamide adenine dinucleotide (NAD) concentrations potentially provide another sensitive indicator of niacin depletion, although definitions of deficient, low and adequate have not been established. Lastly, plasma tryptophan decreases on a low niacin diet because tryptophan converts to niacin. However, low tryptophan could also be caused by a diet low in this essential amino acid, so it is not specific to confirming vitamin status.

Dietary recommendations

Dietary recommendations

Australia and New Zealand

Canada

European Food Safety Authority

United States

The U.S. Institute of Medicine (renamed National Academy of Medicine in 2015) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for niacin in 1998, also Tolerable upper intake levels (ULs). In lieu of an RDA, Adequate Intakes (AIs) are identified for populations for which there is not sufficient evidence to identify a dietary intake level that is sufficient to meet the nutrient requirements of most people. (see table).

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values (DRV), with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. For the EU, AIs and ULs have the same definition as in the US, except that units are milligrams per megajoule (MJ) of energy consumed rather than mg/day. For women (including those pregnant or lactating), men and children the PRI is 1.6 mg per megajoule. As the conversion is 1 MJ = 239 kcal, an adult consuming 2390 kilocalories should be consuming 16 mg niacin. This is comparable to US RDAs (14 mg/day for adult women, 16 mg/day for adult men).

ULs are established by identifying amounts of vitamins and minerals that cause adverse effects, and then selecting as an upper limit amounts that are the "maximum daily intake unlikely to cause adverse health effects." Regulatory agencies from different countries do not always agree. For the US, 30 or 35 mg for teenagers and adults, less for children. The EFSA UL for adults is set at 10 mg/day - about one-third of the US value. For all of the government ULs, the term applies to niacin as a supplement consumed as one dose, and is intended as a limit to avoid the skin flush reaction. This explains why for EFSA, the recommended daily intake can be higher than the UL.

Both the DRI and DRV describe amounts needed as niacin equivalents (NE), calculated as 1 mg NE = 1 mg niacin or 60 mg of the essential amino acid tryptophan. This is because the amino acid is utilized to synthesize the vitamin.

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For niacin labeling purposes 100% of the Daily Value is 16 mg. Prior to 27 May 2016 it was 20 mg, revised to bring it into agreement with the RDA. Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at Reference Daily Intake.

Sources

Niacin is found in a variety of whole and processed foods, including fortified packaged foods, meat from various animal sources, seafoods, and spices. In general, animal-sourced foods provide about 5–10 mg niacin per serving, although dairy foods and eggs have little. Some plant-sourced foods such as nuts, legumes and grains provide about 2–5 mg niacin per serving, although in some grain products this naturally present niacin is largely bound to polysaccharides and glycopeptides, making it only about 30% bioavailable. Fortified food ingredients such as wheat flour have niacin added, which is bioavailable. Among whole food sources with the highest niacin content per 100 grams:

Source	Amount (mg / 100g)
Nutritional yeast Serving = 2 Tbsp (16 g) contains 56 mg	350
Tuna, yellowfin	22.1
Peanuts	14.3
Peanut butter	13.1
Bacon	10.4
Tuna, light, canned	10.1
Salmon	10.0
Turkey depending on what part, how cooked	7-12
Chicken depending on what part, how cooked	7-12

Source	Amount (mg / 100g)
Beef depending on what part, how cooked	4-8
Pork depending on what part, how cooked	4-8
Sunflower seeds	7.0
Tuna, white, canned	5.8
Almonds	3.6
Mushrooms, white	3.6
Cod fish	2.5
Rice, brown	2.5
Hot dogs	2.0

Source	Amount (mg / 100g)
Avocado	1.7
Potato, baked, with skin	1.4
Corn (maize)	1.0
Rice, white	0.5
Kale	0.4
Eggs	0.1
Milk	0.1
Cheese	0.1
Tofu	0.1

Vegetarian and vegan diets can provide adequate amounts if products such as nutritional yeast, peanuts, peanut butter, tahini, brown rice, mushrooms, avocado and sunflower seeds are included. Fortified foods and dietary supplements can also be consumed to ensure adequate intake.

Food preparation

Niacin naturally found in food is susceptible to destruction from high heat cooking, especially in the presence of acidic foods and sauces. It is soluble in water, and so may also be lost from foods boiled in water.

Food fortification

Countries fortify foods with nutrients to address known deficiencies. As of 2020, 54 countries required food fortification of wheat flour with niacin or niacinamide; 14 also mandate fortification of maize flour, and 6 mandate fortification of rice. From country to country, niacin fortification ranges from 1.3 to 6.0 mg/100 g.

As a dietary supplement

In the United States, niacin is sold as a non-prescription dietary supplement with a range of 100 to 1000 mg per serving. These products often have a Structure/Function health claim allowed by the US Food & Drug Administration (FDA). An example would be "Supports a healthy blood lipid profile." The American Heart Association strongly advises against the substitution of dietary supplement niacin for prescription niacin because of potentially serious side effects, which means that niacin should only be used under the supervision of a health care professional, and because manufacture of dietary supplement niacin is not as well-regulated by the FDA as prescription niacin. More than 30 mg niacin consumed as a dietary supplement can cause skin flushing. Face, arms and chest skin turns a reddish color because of vasodilation of small subcutaneous blood vessels, accompanied by sensations of heat, tingling and itching. These signs and symptoms are typically transient, lasting minutes to hours; they are considered unpleasant rather than toxic.

As lipid-modifying medication

In the United States, prescription niacin, in immediate-release and slow-release forms, is used to treat primary hyperlipidemia and hypertriglyceridemia. It is used either as a monotherapy or in combination with other lipid-modifying drugs. Dosages start at 500 mg/day and are often gradually increased to as high as 3000 mg/day for immediate release or 2000 mg/day for slow release (also referred to as sustained release) to achieve the targeted lipid changes (lower LDL-C and triglycerides, and higher HDL-C). Prescriptions in the US peaked in 2009, at 9.4 million and had declined to 800 thousand by 2020.^[18]

Systematic reviews found no effect of prescription niacin on all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes despite raising HDL cholesterol. Reported side effects include an increased risk of new-onset type 2 diabetes.

Mechanisms

Niacin reduces synthesis of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), lipoprotein(a) and triglycerides, and increases high-density lipoprotein cholesterol (HDL-C). The lipid-therapeutic effects of niacin are partly mediated through the activation of G protein-coupled receptors, including hydroxycarboxylic acid receptor 2 (HCA₂)and hydroxycarboxylic acid receptor 3 (HCA₃), which are highly expressed in body fat. HCA₂ and HCA₃ inhibit cyclic adenosine monophosphate (cAMP) production and thus suppress the release of free fatty acids (FFAs) from body fat, reducing their availability to the liver to synthesize the blood-circulating lipids in question. A decrease in free fatty acids also suppresses liver expression of apolipoprotein C3 and PPARg coactivator-1b, thus increasing VLDL-C turnover and reducing its production. Niacin also directly inhibits the action of diacylglycerol O-acyltransferase 2 (DGAT2) a key enzyme for triglyceride synthesis.

The mechanism behind niacin increasing HDL-C is not totally understood, but seems to occur in various ways. Niacin increases apolipoprotein A1 levels by inhibiting the breakdown of this protein, which is a component of HDL-C. It also inhibits HDL-C hepatic uptake by suppressing production of the cholesterol ester transfer protein (CETP) gene. It stimulates the ABCA1 transporter in monocytes and macrophages and upregulates peroxisome proliferator-activated receptor gamma, resulting in reverse cholesterol transport.

Combined with statins

Extended release niacin was combined with lovastatin (Advicor), and with simvastatin (Simcor), as prescription drug combinations. The combination niacin/lovastatin was approved by the U.S. Food and Drug Administration (FDA) in 2001. The combination niacin/simvastatin was approved by the FDA in 2008. Subsequently, large outcome trials using these niacin and statin therapies were unable to demonstrate incremental benefit of niacin beyond statin therapy alone. The FDA withdrew approval of both drugs in 2016. The reason given: "Based on the collective evidence from several large cardiovascular outcome trials, the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events." The drug company discontinued the drugs.

Contraindications

Prescription immediate release (Niacor) and extended release (Niaspan) niacin are contraindicated for people with either active or a history of liver disease because both, but especially Niaspan, have been associated with instances of serious, on occasion fatal, liver failure. Both products are contraindicated for people with existing peptic ulcer disease, or other bleeding problems because niacin lowers platelet count and interferes with blood clotting. Both products are also contraindicated for women who are pregnant or expecting to become pregnant because safety during pregnancy has not been evaluated in human trials. These products are contraindicated for women who are lactating because it is known that niacin is excreted into human milk, but the amount and potential for adverse effects in the nursing infant are not known. Women are advised to either not nurse their child or discontinue the drug. High-dose niacin has not been tested or approved for use in children under 16 years.

Adverse effects

The most common adverse effects of medicinal niacin (500–3000 mg) are flushing (e.g., warmth, redness, itching or tingling) of the face, neck and chest, headache, abdominal pain, diarrhea, dyspepsia, nausea, vomiting, rhinitis, pruritus and rash. These can be minimized by initiating therapy at low dosages, increasing dosage gradually, and avoiding administration on an empty stomach.

The acute adverse effects of high-dose niacin therapy (1–3 grams per day) – which is commonly used in the treatment of hyperlipidemias – can further include hypotension, fatigue, glucose intolerance and insulin resistance, heartburn, blurred or impaired vision, and macular edema. With long-term use, the adverse effects of high-dose niacin therapy (750 mg per day) also include liver failure (associated with fatigue, nausea, and loss of appetite), hepatitis, and acute liver failure; these hepatotoxic effects of niacin occur more often when extended-release dosage forms are used. The long-term use of niacin at greater than or equal to 2 grams per day also significantly increases the risk of cerebral hemorrhage, ischemic stroke, gastrointestinal ulceration and bleeding, diabetes, dyspepsia, and diarrhea.

Flushing

Flushing – a short-term dilatation of skin arterioles, causing reddish skin color – usually lasts for about 15 to 30 minutes, although sometimes can persist for weeks. Typically, the face is affected, but the reaction can extend to neck and upper chest. The cause is blood vessel dilation due to elevation in prostaglandin GD₂ (PGD2) and serotonin. Flushing was often thought to involve histamine, but histamine has been shown not to be involved in the reaction. Flushing is sometimes accompanied by a prickly or itching sensation, in particular, in areas covered by clothing.

Prevention of flushing requires altering or blocking the prostaglandin-mediated pathway. Aspirin taken half an hour before the niacin prevents flushing, as does ibuprofen. Taking niacin with meals also helps reduce this side effect. Acquired tolerance will also help reduce flushing; after several weeks of a consistent dose, most people no longer experience flushing. Slow- or "sustained"-release forms of niacin have been developed to lessen these side effects.

Liver damage

Niacin in medicinal doses can cause modest elevations in serum transaminase and unconjugated bilirubin, both biomarkers of liver injury. The increases usually resolve even when drug intake is continued. However, less commonly, the sustained release form of the drug can lead to serious hepatotoxicity, with onset in days to weeks. Early symptoms of serious liver damage include nausea, vomiting and abdominal pain, followed by jaundice and pruritus. The mechanism is thought to be a direct toxicity of elevated serum niacin. Lowering dose or switching to the immediate release form can resolve symptoms. In rare instances the injury is severe, and progresses to liver failure.

Diabetes

The high doses of niacin used to treat hyperlipidemia have been shown to elevate fasting blood glucose in people with type 2 diabetes. Long-term niacin therapy was also associated with an increase in the risk of new-onset type 2 diabetes.

Other adverse effects

High doses of niacin can also cause niacin maculopathy, a thickening of the macula and retina, which leads to blurred vision and blindness. This maculopathy is reversible after niacin intake ceases. Niaspan, the slow-release product, has been associated with a reduction in platelet content and a modest increase in prothrombin time.

Pharmacology

Pharmacodynamics

Activating HCA₂ has effects other than lowering serum cholesterol and triglyceride concentrations: antioxidative, anti-inflammatory, antithrombotic, improved endothelial function and plaque stability, all of which counter development and progression of atherosclerosis.

Niacin inhibits cytochrome P450 enzymes CYP2E1, CYP2D6 and CYP3A4. Niacin produces a rise in serum unconjugated bilirubin in normal individuals and in those with Gilbert's Syndrome. However, in the Gilbert's Syndrome, the rise in bilirubin is higher and clearance is delayed longer than in normal people. One test used to aid in diagnosing Gilbert's Syndrome involves intravenous administration of nicotinic acid (niacin) in a dose of 50 mg over a period of 30 seconds.

See also: Niacin § Liver_damage

Pharmacokinetics

Both niacin and niacinamide are rapidly absorbed from the stomach and small intestine. Absorption is facilitated by sodium-dependent diffusion, and at higher intakes, via passive diffusion. Unlike some other vitamins, the percent absorbed does not decrease with increasing dose, so that even at amounts of 3-4 grams, absorption is nearly complete. With a one gram dose, peak plasma concentrations of 15 to 30 μg/mL are reached within 30 to 60 minutes. Approximately 88% of an oral pharmacologic dose is eliminated by the kidneys as unchanged niacin or nicotinuric acid, its primary metabolite. The plasma elimination half-life of niacin ranges from 20 to 45 minutes.

Niacin and nicotinamide are both converted into the coenzyme NAD. NAD converts to NADP by phosphorylation in the presence of the enzyme NAD+ kinase. High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency. In the liver, niacinamide is converted to storage nicotinamide adenine dinucleotide (NAD). As needed, liver NAD is hydrolyzed to niacinamide and niacin for transport to tissues, there reconverted to NAD to serve as an enzyme cofactor. Excess niacin is methylated in the liver to N¹-methylnicotinamide (NMN) and excreted in urine as such or as the oxidized metabolite N¹-methyl-2-pyridone-5-carboxamide (2-pyridone). Decreased urinary content of these metabolites is a measure of niacin deficiency.

Niacin, serotonin (5-hydroxytryptamine), and melatonin biosynthesis from tryptophan

Production

Biosynthesis

In addition to absorbing niacin from diet, niacin can be synthesized from the essential amino acid tryptophan, a five-step process with the penultimate compound being quinolinic acid (see figure). Some bacteria and plants utilize aspartic acid in a pathway that also goes to quinolinic acid. For humans, the efficiency of conversion is estimated as requiring 60 mg of tryptophan to make 1 mg of niacin. Riboflavin, vitamin B₆ and iron are required for the process. Pellagra is a consequence of a corn-dominant diet because the niacin in corn is poorly bioavailable and corn proteins are low in tryptophan compared to wheat and rice proteins.

Industrial synthesis

Nicotinic acid was first synthesized in 1867 by oxidative degradation of nicotine. Niacin is prepared by hydrolysis of nicotinonitrile, which, as described above, is generated by oxidation of 3-picoline. Oxidation can be effected by air, but ammoxidation is more efficient. In the latter process, nicotinonitrile is produced by ammoxidation of 3-methylpyridine. Nitrile hydratase is then used to catalyze nicotinonitrile to nicotinamide, which can be converted to niacin. Alternatively, ammonia, acetic acid and paraldehyde are used to make 5-ethyl-2-methyl-pyridine, which is then oxidized to niacin. New "greener" catalysts are being tested using manganese-substituted aluminophosphates that use acetyl peroxyborate as non-corrosive oxidant, avoiding producing nitrogen oxides as do traditional ammoxidations.

The demand for commercial production includes for animal feed and for food fortification meant for human consumption. According to Ullmann's Encyclopedia of Industrial Chemistry, worldwide 31,000 tons of nicotinamide were sold in 2014.

Chemistry

This colorless, water-soluble solid is a derivative of pyridine, with a carboxyl group (COOH) at the 3-position. Other forms of vitamin B₃ include the corresponding amide nicotinamide (niacinamide), where the carboxyl group has been replaced by a carboxamide group (CONH
₂).

Preparations

Niacin is incorporated into multi-vitamin and sold as a single-ingredient dietary supplement. The latter can be immediate or slow release.

Nicotinamide (niacinamide) is used to treat niacin deficiency because it does not cause the flushing adverse reaction seen with niacin. Nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults.

Prescription products can be immediate release (Niacor, 500 mg tablets) or extended release (Niaspan, 500 and 1000 mg tablets). Niaspan has a film coating that delays release of the niacin, resulting in an absorption over a period of 8–12 hours. This reduces vasodilation and flushing side effects, but increases the risk of hepatotoxicity compared to the immediate release drug.

Prescription niacin in combination with statin drugs (discontinued) is described above. A combination of niacin and laropiprant had been approved for use in Europe and marketed as Tredaptive. Laropiprant is a prostaglandin D2 binding drug shown to reduce niacin-induced vasodilation and flushing side effects. A clinical trial showed no additional efficacy of Tredaptive in lowering cholesterol when used together with other statin drugs, but did show an increase in other side effects. The study resulted in the withdrawal of Tredaptive from the international market.

Inositol hexanicotinate

One form of dietary supplement sold in the US is inositol hexanicotinate (IHN), also called inositol nicotinate. This is inositol that has been esterified with niacin on all six of inositol's alcohol groups. IHN is usually sold as "flush-free" or "no-flush" niacin in units of 250, 500, or 1000 mg/tablets or capsules. In the US, it is sold as an over-the-counter formulation, and often is marketed and labeled as niacin, thus misleading consumers into thinking they are getting an active form of the medication. While this form of niacin does not cause the flushing associated with the immediate-release products, there is not enough evidence to recommend IHN to treat hyperlipidemia.

History

Further information: Vitamin § History

Niacin as a chemical compound was first described by chemist Hugo Weidel in 1873 in his studies of nicotine, but that predated by many years the concept of food components other than protein, fat and carbohydrates that were essential for life. Vitamin nomenclature was initially alphabetical, with Elmer McCollum calling these fat-soluble A and water-soluble B. Over time, eight chemically distinct, water-soluble B vitamins were isolated and numbered, with niacin as vitamin B₃.

Further information: Pellagra § History

Corn (maize) became a staple food in the southeast United States and in parts of Europe. A disease that was characterized by dermatitis of sunlight-exposed skin was described in Spain in 1735 by Gaspar Casal. He attributed the cause to poor diet. In northern Italy it was named "pellagra" from the Lombard language (agra = holly-like or serum-like; pell = skin). In time, the disease was more closely linked specifically to corn. In the US, Joseph Goldberger was assigned to study pellagra by the Surgeon General of the United States. His studies confirmed a corn-based diet as the culprit, but he did not identify the root cause.

Nicotinic acid was extracted from liver by biochemist Conrad Elvehjem in 1937. He later identified the active ingredient, referring to it as "pellagra-preventing factor" and the "anti-blacktongue factor." It was also referred to as "vitamin PP", "vitamin P-P" and "PP-factor", all derived from the term "pellagra-preventive factor". In the late 1930s, studies by Tom Douglas Spies, Marion Blankenhorn, and Clark Cooper confirmed that niacin cured pellagra in humans. The prevalence of the disease was greatly reduced as a result.

In 1942, when flour enrichment with nicotinic acid began, a headline in the popular press said "Tobacco in Your Bread." In response, the Council on Foods and Nutrition of the American Medical Association approved of the Food and Nutrition Board's new names niacin and niacin amide for use primarily by non-scientists. It was thought appropriate to choose a name to dissociate nicotinic acid from nicotine, to avoid the perception that vitamins or niacin-rich food contains nicotine, or that cigarettes contain vitamins. The resulting name niacin was derived from nicotinic acid + vitamin.

Carpenter found in 1951, that niacin in corn is biologically unavailable, and can be released only in very alkaline lime water of pH 11. This explains why a Latin-American culture that used alkali-treated cornmeal to make tortilla was not at risk for niacin deficiency.

In 1955, Altschul and colleagues described large amounts of niacin as having a lipid-lowering property. As such, niacin is the oldest known lipid-lowering drug. Lovastatin, the first 'statin' drug, was first marketed in 1987.

Research

In animal models and in vitro, niacin produces marked anti-inflammatory effects in a variety of tissues – including the brain, gastrointestinal tract, skin, and vascular tissue – through the activation of hydroxycarboxylic acid receptor 2 (HCA2), also known as niacin receptor 1 (NIACR1). Unlike niacin, nicotinamide does not activate NIACR1; however, both niacin and nicotinamide activate the G protein-coupled estrogen receptor (GPER) in vitro.