Nicotinamide adenine dinucleotide hydrogen

Nicotinamide adenine dinucleotide (NAD) is a cofactor 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.

Physical and chemical properties

Nicotinamide adenine dinucleotide consists of two nucleosides joined by a pair of bridging phosphate groups. 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. 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 β-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.

Extracellular actions of NAD

In recent years, NAD+ has also been recognized as an extracellular signaling molecule involved in cell-to-cell communication.[41][75][76] NAD+ is released from neurons in blood vessels,[40] urinary bladder,[40][77] large intestine,[78][79] from neurosecretory cells,[80] and from brain synaptosomes,[81] and is proposed to be a novel neurotransmitter that transmits information from nerves to effector cells in smooth muscle organs.[78][79] In plants, the extracellular nicotinamide adenine dinucleotide induces resistance to pathogen infection and the first extracellular NAD receptor has been identified.[82] 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.[83] 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.[84]

Because cancer cells utilize increased glycolysis, and because NAD enhances glycolysis, nicotinamide phosphoribosyltransferase (NAD salvage pathway) is often amplified in cancer cells.[85][86]

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.[91] 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.[91][92] 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.[93] Compounds such as resveratrol increase the activity of these enzymes, which may be important in their ability to delay aging in both vertebrate,[94] and invertebrate model organisms.[95][96] In one experiment, mice given NAD for one week had improved nuclear-mitochrondrial communication.[97]

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.[98][99] 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.[35] In bacteriology, NAD, sometimes referred to factor V, is used a supplement to culture media for some fastidious bacteria.[100]

History

The coenzyme NAD+ was first discovered by the British biochemists Arthur Harden and William John Young in 1906.[101] 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.[102] 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.[103]

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.[104] Then, in 1939, he provided the first strong evidence that niacin is used to synthesize NAD+.[105] In the early 1940s, Arthur Kornberg was the first to detect an enzyme in the biosynthetic pathway.[106] 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.[107] In 1958, Jack Preiss and Philip Handler discovered the intermediates and enzymes involved in the biosynthesis of NAD+;[108][109] 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+.[110]

The non-redox roles of NAD(P) were discovered later.[1] The first to be identified was the use of NAD+ as the ADP-ribose donor in ADP-ribosylation reactions, observed in the early 1960s.[111] 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.[112]

The metabolism of 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.[113] 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).[114] 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.[115]

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