Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism.
Nicotinamide adenine dinucleotide (NAD) is a crucial coenzyme found in all living cells.
It’s a small molecule that plays fundamental roles in cellular metabolism and energy production.
NAD is found in all living cells and is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups.
NAD exists in two main forms: NAD+** (oxidized form) – the electron acceptor
NADH** (reduced form) – the electron donor
NAD is involved in redox reactions, carrying electrons from one reaction to another, so it is found in two forms: NAD+ is an oxidizing agent, accepting electrons from other molecules and becoming reduced; with H+, this reaction forms NADH, which can be used as a reducing agent to donate electrons.
Electron transfer reactions are the main function of NAD.
It is also used in other cellular processes: as a substrate of enzymes in adding or removing chemical groups to or from proteins, in posttranslational modifications.
Beyond its role in energy metabolism, NAD is a substrate for enzymes like poly(ADP-ribose) polymerases (PARPs), sirtuins, and CD38, regulating DNA repair, gene expression, and stress responses.
It is also involved in post-translational modifications and intracellular signaling.
NAD can be synthesized de novo from amino acids like tryptophan or aspartic acid or recycled via salvage pathways using precursors like nicotinic acid or nicotinamide.
Some NAD is converted into NADP, which plays a key role in anabolic reactions.
Some NAD is converted into the coenzyme nicotinamide adenine dinucleotide phosphate (NADP).
In the name NAD+, the superscripted plus sign indicates the positive formal charge on one of its nitrogen atoms.
A biological coenzyme that acts as an electron carrier in enzymatic reactions.
NADP is a reducing agent in anabolic reactions.
NADP exists in two forms: NADP+, the oxidized form, and NADPH, the reduced form. NADP is similar to nicotinamide adenine dinucleotide (NAD), but NADP has a phosphate group at the C-2′ position of the adenosyl.
The molecule consists of two nucleotides joined together: one contains adenine (a purine base) and the other contains nicotinamide (derived from niacin/vitamin B3).
The compound accepts or donates the equivalent of H−.
The coenzyme can continuously cycle between the NAD+ and NADH forms without being consumed.
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 balance between the oxidized and reduced forms of nicotinamide adenine dinucleotide is called the NAD+/NADH ratio, and 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 NAD+/NADH ratio controls the activity of several key enzymes, including glyceraldehyde 3-phosphate dehydrogenase and pyruvate dehydrogenase.
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.
NAD+ is synthesized through two metabolic pathways:de novo pathway from amino acids or in salvage pathways by recycling preformed components such as nicotinamide back to NAD+.
Most tissues synthesize NAD+ by the salvage pathway , much more de novo synthesis occurs in the liver from tryptophan, and in the kidney and macrophages from nicotinic acid.
In most organisms, this enzyme uses adenosine triphosphate (ATP) as the source of the phosphate group.
Salvage reactions are essential in humans; a lack of vitamin B3 in the diet causes the vitamin deficiency disease pellagra.
The high requirement for NAD+ results from the constant consumption of the coenzyme in reactions such as posttranslational modifications: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+ is the salvage pathway which recycles the nicotinamide produced by enzymes utilizing NAD+.
The three vitamin precursors used in 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.
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.
NAD is essential for cellular respiration.
In glycolysis and the citric acid cycle, NAD+ accepts electrons and hydrogen ions from glucose breakdown, becoming NADH.
This NADH then delivers those electrons to the electron transport chain in mitochondria, where ATP cellular energy is produced.
NAD serves as a shuttle for electrons in hundreds of metabolic reactions.
NAD alternates between its oxidized (NAD+) and reduced (NADH) forms, making it central to the cell’s ability to extract energy from nutrients.
NAD+ is involved in:
DNA repair mechanisms
Gene expression regulation
Cellular signaling pathways
Aging processes-NAD+ levels decline with age?
Immune function
Some studies suggest that boosting NAD+ levels might have anti-aging effects, though this research is still developing.
The body can synthesize NAD from dietary sources including niacin (vitamin B3), tryptophan, and newer precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).
Nicotinamide adenine dinucleotide has several essential roles in metabolism: 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.
NAD+ emerges as an adenine nucleotide that can be released from cells spontaneously and by regulated mechanisms, and hasimportant extracellular roles.
The main role of NAD+ in metabolism is the transfer of electrons from one molecule to another which are catalyzed by a large group of enzymes called oxidoreductases.
These enzymes are also referred to as dehydrogenases or reductases, with NADH-ubiquinone oxidoreductase commonly being called NADH dehydrogenase or sometimes coenzyme Q reductase.
The redox metabolism reactions catalyzed by oxidoreductases are vital for the release of energy from nutrients: 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.
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.
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.
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.
The decline in cellular concentrations of NAD+ during aging likely contributes to the aging process and to the pathogenesis of the chronic diseases of aging.
The modulation of NAD+ may protect against cancer, radiation, and aging.
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.
Because cancer cells utilize increased glycolysis, and because NAD enhances glycolysis, nicotinamide phosphoribosyltransferase (NAD salvage pathway) is often amplified in cancer cells.
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.
Because of the importance of this enzyme in purine metabolism, these compounds may be useful as anti-cancer, anti-viral, or immunosuppressive drugs.