14 December 2023
Nicotinamide adenine dinucleotide (abbr. NAD, English Nicotinamide adenine dinucleotide, abbreviated NAD, obsolete diphosphopyridine nucleotide, DPN, DPN) is a coenzyme found in all living cells. NAD is a dinucleotide and consists of two nucleotides connected by their phosphate groups. One of the nucleotides contains adenine as a nitrogenous base, the other contains nicotinamide. Nicotinamide adenine dinucleotide exists in two forms: oxidized (NAD+, NADox) and reduced (NADH, NADred).
Nicotinamide adenine dinucleotide (abbr. NAD, English Nicotinamide adenine dinucleotide, abbreviated NAD, obsolete diphosphopyridine nucleotide, DPN, DPN) is a coenzyme found in all living cells. NAD is a dinucleotide and consists of two nucleotides connected by their phosphate groups. One of the nucleotides contains adenine as a nitrogenous base, the other contains nicotinamide. Nicotinamide adenine dinucleotide exists in two forms: oxidized (NAD+, NADox) and reduced (NADH, NADred).
![anatmy of a cell anatmy of a cell](data:image/gif;base64,R0lGODlhAQABAAAAACH5BAEKAAEALAAAAAABAAEAAAICTAEAOw==)
In metabolism, NAD is involved in redox reactions, transferring electrons from one reaction to another. Thus, in cells, NAD exists in two functional states: its oxidized form, NAD+, is an oxidizing agent and takes electrons from another molecule, being reduced to NADH, which then serves as a reducing agent and donates electrons. Such reactions involving electron transfer are the main area of action of NAD. However, NAD has other functions in the cell, in particular, it serves as a substrate for enzymes that remove or add chemical groups to proteins during post-translational modifications. Due to the importance of NAD functions, enzymes involved in its metabolism are targets for the search for new drugs.
In living organisms, NAD is synthesized de novo[en] from the amino acids aspartate or tryptophan. Other coenzyme precursors enter the body exogenously, such as the vitamin niacin (vitamin B3) from food. Similar compounds are formed in reactions leading to the breakdown of NAD. After this, such compounds undergo a recycling pathway that returns them to their active form. Some NAD molecules are converted to nicotinamide adenine dinucleotide phosphate (NADP). This coenzyme, closely related to NAD, is chemically similar to it, but they perform different functions in metabolism.
Although NAD+ is written with a plus sign due to the formal positive charge of the nitrogen atom, at physiological pH most NAD+ is actually an anion with a negative charge of 1, and NADH is an anion with a charge of 2.
NAD is called the “V factor” necessary for the growth of Haemophilus influenzae. Enzymes involved in the synthesis and use of NAD+ are important for pharmacology and research aimed at finding new ways to treat diseases [76]. When developing new drugs[en], NAD+ is considered from three perspectives: as a direct target for drugs, for the development of enzyme inhibitors and activators, which, due to their structure, change the activity of NAD-dependent enzymes, and for studying methods for suppressing NAD+ biosynthesis [77].
Currently, NAD+ coenzyme itself is not used to treat any disease. However, its potential role in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease is being studied[3]. There are various data on the action of NAD+ in neurodegenerative diseases. Some studies in mice have shown encouraging results[78], but clinical trials in humans using a placebo have failed to show any effect[79].
NAD+ is also a direct target of the drug isoniazid, which is used to treat tuberculosis, an infection caused by the bacterium Mycobacterium tuberculosis. Isoniazid is a prodrug and when it enters a bacterial cell it is activated by peroxidase[en], which oxidizes this substance into a free radical form[80]. This radical further reacts with NADH to form adducts that are very potent inhibitors of the enzymes enoyl-acyl transport protein reductase[en][81] and dihydrofolate reductase[82]. In one experiment, mice given NAD for a week had improved interactions between the cell nucleus and mitochondria[83].
Due to the huge number of oxidoreductases that use NAD+ and NADH as substrates and bind to them using a single highly conserved structural motif, the idea of developing an inhibitor that blocks the NAD+ binding site and is specific only for a particular enzyme seems dubious [84]. However, this may be feasible: for example, inhibitors based on mycophenolic acid[en] and thiazofurin[en] inhibit inosine monophosphate dehydrogenase[en] at the NAD+ binding site. Due to the important role of this enzyme in purine metabolism, these compounds may be useful anticancer and antiviral drugs or immunosuppressants[84][85]. Other drugs are not inhibitors, but, on the contrary, activators of enzymes involved in NAD+ metabolism. In particular, sirtuins may be an interesting target for such drugs, since activation of these NAD-dependent deacetylases increases lifespan[86]. Compounds such as resveratrol increase the activity of these enzymes, which may be important due to their ability to delay aging in both vertebrates[87] and invertebrate model organisms[88][89].
Due to differences in NAD+ biosynthetic pathways among different organisms, particularly between bacteria and humans, NAD+ biosynthesis may be an emerging area for the development of new antibiotics[90][91]. For example, the enzyme nicotinamidase[en], which converts nicotinamide into nicotinic acid, serves as a target for drugs being developed, since this enzyme is absent in humans, but is present in bacteria and yeast[30].
Story
Arthur Harden, one of the pioneers of NAD+
The NAD+ coenzyme was discovered by English biochemists Arthur Harden and William John Young[en] in 1906[92]. They noticed that adding boiled and filtered yeast extract to unboiled extracts significantly increased alcoholic fermentation in the latter. They called the unknown factor responsible for this phenomenon a coenzyme. Through a lengthy and complex process of isolation from yeast extracts, this heat-stable factor was identified as nucleotide sugar phosphate by Hans von Euler-Helpin[93]. In 1936, the German scientist Otto Heinrich Warburg established the function of this coenzyme in the transfer of hydride ions and determined that the nicotinamide residue is involved in redox reactions [94].
The source of nicotinamide was identified in 1938 when Conrad Elvedge[en] isolated niacin from the liver and showed that this vitamin contains nicotinic acid and nicotinamide[95]. Later, in 1939, he provided the first convincing evidence that niacin is used to form NAD+[96]. In the early 1940s, Arthur Kornberg took the next step towards understanding the role of NAD+ in metabolism: he was the first to establish the presence of this coenzyme in biosynthetic pathways[97]. Further, in 1949, American biochemists Morris Friedkin and Albert Lehninger proved that NAD+ is associated with metabolic pathways such as the tricarboxylic acid cycle and oxidative phosphorylation[98]. Finally, in 1959, Jack Preiss and Philip Handler described the enzymes and intermediates of NAD+ biosynthesis[99][100], so the de novo NAD+ synthesis pathway is often called the Priss-Handler pathway in their honor.
The functions of NAD and NADP, not related to redox reactions, were discovered only recently[2]. The first discovered function of NAD+ was to participate as a donor of the ADP-ribose residue in ADP-ribosylation reactions; this was established in the early 1960s[101]. More recent studies in the 1980s and 1990s implicated NAD+ and NADP+ in cell-cell signal transduction. In particular, the effect of cyclic ADP-ribose was established in 1987[102]. NAD+ metabolism remains an area of intense research into the 21st century. This interest especially increased after the discovery in 2000 of NAD+-dependent deacetylases, sirtuins, by Shinichiro Imai and collaborators at the Massachusetts Institute of Technology [103].
![anatmy of a cell anatmy of a cell](/upload/medialibrary/f55/f552bfb06f6b5f13ec1b5a0d8bbff127.jpg)
In metabolism, NAD is involved in redox reactions, transferring electrons from one reaction to another. Thus, in cells, NAD exists in two functional states: its oxidized form, NAD+, is an oxidizing agent and takes electrons from another molecule, being reduced to NADH, which then serves as a reducing agent and donates electrons. Such reactions involving electron transfer are the main area of action of NAD. However, NAD has other functions in the cell, in particular, it serves as a substrate for enzymes that remove or add chemical groups to proteins during post-translational modifications. Due to the importance of NAD functions, enzymes involved in its metabolism are targets for the search for new drugs.
In living organisms, NAD is synthesized de novo[en] from the amino acids aspartate or tryptophan. Other coenzyme precursors enter the body exogenously, such as the vitamin niacin (vitamin B3) from food. Similar compounds are formed in reactions leading to the breakdown of NAD. After this, such compounds undergo a recycling pathway that returns them to their active form. Some NAD molecules are converted to nicotinamide adenine dinucleotide phosphate (NADP). This coenzyme, closely related to NAD, is chemically similar to it, but they perform different functions in metabolism.
Although NAD+ is written with a plus sign due to the formal positive charge of the nitrogen atom, at physiological pH most NAD+ is actually an anion with a negative charge of 1, and NADH is an anion with a charge of 2.
NAD is called the “V factor” necessary for the growth of Haemophilus influenzae. Enzymes involved in the synthesis and use of NAD+ are important for pharmacology and research aimed at finding new ways to treat diseases [76]. When developing new drugs[en], NAD+ is considered from three perspectives: as a direct target for drugs, for the development of enzyme inhibitors and activators, which, due to their structure, change the activity of NAD-dependent enzymes, and for studying methods for suppressing NAD+ biosynthesis [77].
Currently, NAD+ coenzyme itself is not used to treat any disease. However, its potential role in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease is being studied[3]. There are various data on the action of NAD+ in neurodegenerative diseases. Some studies in mice have shown encouraging results[78], but clinical trials in humans using a placebo have failed to show any effect[79].
NAD+ is also a direct target of the drug isoniazid, which is used to treat tuberculosis, an infection caused by the bacterium Mycobacterium tuberculosis. Isoniazid is a prodrug and when it enters a bacterial cell it is activated by peroxidase[en], which oxidizes this substance into a free radical form[80]. This radical further reacts with NADH to form adducts that are very potent inhibitors of the enzymes enoyl-acyl transport protein reductase[en][81] and dihydrofolate reductase[82]. In one experiment, mice given NAD for a week had improved interactions between the cell nucleus and mitochondria[83].
Due to the huge number of oxidoreductases that use NAD+ and NADH as substrates and bind to them using a single highly conserved structural motif, the idea of developing an inhibitor that blocks the NAD+ binding site and is specific only for a particular enzyme seems dubious [84]. However, this may be feasible: for example, inhibitors based on mycophenolic acid[en] and thiazofurin[en] inhibit inosine monophosphate dehydrogenase[en] at the NAD+ binding site. Due to the important role of this enzyme in purine metabolism, these compounds may be useful anticancer and antiviral drugs or immunosuppressants[84][85]. Other drugs are not inhibitors, but, on the contrary, activators of enzymes involved in NAD+ metabolism. In particular, sirtuins may be an interesting target for such drugs, since activation of these NAD-dependent deacetylases increases lifespan[86]. Compounds such as resveratrol increase the activity of these enzymes, which may be important due to their ability to delay aging in both vertebrates[87] and invertebrate model organisms[88][89].
Due to differences in NAD+ biosynthetic pathways among different organisms, particularly between bacteria and humans, NAD+ biosynthesis may be an emerging area for the development of new antibiotics[90][91]. For example, the enzyme nicotinamidase[en], which converts nicotinamide into nicotinic acid, serves as a target for drugs being developed, since this enzyme is absent in humans, but is present in bacteria and yeast[30].
Story
Arthur Harden, one of the pioneers of NAD+
The NAD+ coenzyme was discovered by English biochemists Arthur Harden and William John Young[en] in 1906[92]. They noticed that adding boiled and filtered yeast extract to unboiled extracts significantly increased alcoholic fermentation in the latter. They called the unknown factor responsible for this phenomenon a coenzyme. Through a lengthy and complex process of isolation from yeast extracts, this heat-stable factor was identified as nucleotide sugar phosphate by Hans von Euler-Helpin[93]. In 1936, the German scientist Otto Heinrich Warburg established the function of this coenzyme in the transfer of hydride ions and determined that the nicotinamide residue is involved in redox reactions [94].
The source of nicotinamide was identified in 1938 when Conrad Elvedge[en] isolated niacin from the liver and showed that this vitamin contains nicotinic acid and nicotinamide[95]. Later, in 1939, he provided the first convincing evidence that niacin is used to form NAD+[96]. In the early 1940s, Arthur Kornberg took the next step towards understanding the role of NAD+ in metabolism: he was the first to establish the presence of this coenzyme in biosynthetic pathways[97]. Further, in 1949, American biochemists Morris Friedkin and Albert Lehninger proved that NAD+ is associated with metabolic pathways such as the tricarboxylic acid cycle and oxidative phosphorylation[98]. Finally, in 1959, Jack Preiss and Philip Handler described the enzymes and intermediates of NAD+ biosynthesis[99][100], so the de novo NAD+ synthesis pathway is often called the Priss-Handler pathway in their honor.
The functions of NAD and NADP, not related to redox reactions, were discovered only recently[2]. The first discovered function of NAD+ was to participate as a donor of the ADP-ribose residue in ADP-ribosylation reactions; this was established in the early 1960s[101]. More recent studies in the 1980s and 1990s implicated NAD+ and NADP+ in cell-cell signal transduction. In particular, the effect of cyclic ADP-ribose was established in 1987[102]. NAD+ metabolism remains an area of intense research into the 21st century. This interest especially increased after the discovery in 2000 of NAD+-dependent deacetylases, sirtuins, by Shinichiro Imai and collaborators at the Massachusetts Institute of Technology [103].
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