Is there a difference between NADH and NADH2?

Is there a difference between NADH and NADH2?

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I've been reading a lot about the oxidative dissimilation etc, and often I see different sources use NADH and NADH2 in the same reactions. One source uses NADH and another uses NADH2 in the exact same way. Is there a difference or is it just a different name for the same substance?

They are often used interchangeably to indicate the reduced form of $ce{NAD+}$. The overall reaction when oxidizing some molecule $ce{RH2}$ is: $ce{RH2 + NAD+ -> NADH + H+ + R}$. The proper reduced $ce{NAD+}$ is $ce{NADH}$ (it accepts two electrons and one proton), but sometimes $ce{NADH2}$ is used to account for that second hydrogen that gets removed from the substrate being oxidized. The notation $ce{NADH2}$ doesn't really take into account the fact that the second hydrogen is charged, and not bound to the $ce{NAD}$ in the same way that the first hydrogen is, so it is confusing. The notation: "$ce{NADH + H+}$" is more correct and is also sometimes used.

What is the difference between NAD+ and NADH?

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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. [1] [2]

The compound accepts or donates the equivalent of H − . [3] 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.

From the hydride electron pair, one electron is transferred to the positively charged nitrogen of the nicotinamide ring of NAD + , and the second hydrogen atom transferred to the C4 carbon atom opposite this nitrogen. The midpoint potential of the NAD + /NADH redox pair is −0.32 volts, which makes NADH a strong reducing agent. [4] 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. [2]

In appearance, all forms of this coenzyme are white amorphous powders that are hygroscopic and highly water-soluble. [5] The solids are stable if stored dry and in the dark. Solutions of NAD + are colorless and stable for about a week at 4 °C and neutral pH, but decompose rapidly in acids or alkalis. Upon decomposition, they form products that are enzyme inhibitors. [6]

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 −1 cm −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 −1 cm −1 . [7] 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. [7]

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. [8] [9] 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. [9] [10] These changes in fluorescence are also used to measure changes in the redox state of living cells, through fluorescence microscopy. [11]

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. [12] The actual concentration of NAD + in cell cytosol is harder to measure, with recent estimates in animal cells ranging around 0.3 mM, [13] [14] and approximately 1.0 to 2.0 mM in yeast. [15] However, more than 80% of NADH fluorescence in mitochondria is from bound form, so the concentration in solution is much lower. [16]

NAD + concentrations are highest in the mitochondria, constituting 40% to 70% of the total cellular NAD + . [17] NAD + in the cytosol is carried into the mitochondrion by a specific membrane transport protein, since the coenzyme cannot diffuse across membranes. [18] The intracellular half-life of NAD + was claimed to be between 1–2 hours by one review, [19] whereas another review gave varying estimates based on compartment: intracellular 1–4 hours, cytoplasmic 2 hours, and mitochondrial 4–6 hours. [20]

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. [21] The effects of the NAD + /NADH ratio are complex, controlling the activity of several key enzymes, including glyceraldehyde 3-phosphate dehydrogenase and pyruvate dehydrogenase. In healthy mammalian tissues, estimates of the ratio between free NAD + and NADH in the cytoplasm typically lie around 700:1 the ratio is thus favourable for oxidative reactions. [22] [23] The ratio of total NAD + /NADH is much lower, with estimates ranging from 3–10 in mammals. [24] In contrast, the NADP + /NADPH ratio is normally about 0.005, so NADPH is the dominant form of this coenzyme. [25] These different ratios are key to the different metabolic roles of NADH and NADPH.

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. [26]

De novo production Edit

Most organisms synthesize NAD + from simple components. [3] 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. [27] [28] 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. [3]

In a further step, some NAD + is converted into NADP + by NAD + kinase, which phosphorylates NAD + . [29] 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. [30] [31]

Salvage pathways Edit

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. [32] 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. [3] The major source of NAD + in mammals is the salvage pathway which recycles the nicotinamide produced by enzymes utilizing NAD + . [33] The first step, and the rate-limiting enzyme in the salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT), which produces nicotinamide mononucleotide (NMN). [33] NMN is the immediate precursor to NAD+ in the salvage pathway. [34]

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). [3] 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. [35] There are some reports that mammalian cells can take up extracellular NAD + from their surroundings, [36] and both nicotinamide and nicotinamide riboside can be absorbed from the gut. [37]

The salvage pathways used in microorganisms differ from those of mammals. [38] 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. [39] [40] 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. [41]

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, [43] [44] and can therefore have important extracellular roles. [44]

Oxidoreductase binding of NAD Edit

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. [45] 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. [46]

There are many different superfamilies of enzymes that bind NAD + / NADH. One of the most common superfamilies include a structural motif known as the Rossmann fold. [47] [48] The motif is named after Michael Rossmann who was the first scientist to notice how common this structure is within nucleotide-binding proteins. [49]

An example of a NAD-binding bacterial enzyme involved in amino acid metabolism that does not have Rossmann fold is found in Pseudomonas syringae pv. tomato ( PDB: 2CWH ​ InterPro: IPR003767). [50]

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. [51]

Despite the similarity in how proteins bind the two coenzymes, enzymes almost always show a high level of specificity for either NAD + or NADP + . [52] 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. [53]

Role in redox metabolism Edit

The redox reactions catalyzed by oxidoreductases are vital in all parts of metabolism, but one particularly important function of these reactions is to enable nutrients to unlock the energy stored in the relatively weak double bond of oxygen. [54] Here, reduced compounds such as glucose and fatty acids are oxidized, thereby releasing the chemical energy of O2. In this process, NAD + is reduced 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. [55] 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. [56] These shuttle systems also have the same transport function in chloroplasts. [57]

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. [58] 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. [58]

Although it is important in catabolism, NADH is also used in anabolic reactions, such as gluconeogenesis. [59] 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. [60] 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. [61]

Non-redox roles Edit

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. [62] 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. [63] 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. [64] [65] Poly(ADP-ribosyl)ation is carried out by the poly(ADP-ribose) polymerases. [63] [66] 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. [66] In addition to these functions within the cell, a group of extracellular ADP-ribosyltransferases has recently been discovered, but their functions remain obscure. [67] NAD + may also be added onto cellular RNA as a 5'-terminal modification. [68]

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. [69] This molecule acts in calcium signaling by releasing calcium from intracellular stores. [70] 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. [71]

NAD + is also consumed by sirtuins, which are NAD-dependent deacetylases, such as Sir2. [72] 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. [73] 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. [74]

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. [75] This contrasts with eukaryotic DNA ligases, which use ATP to form the DNA-AMP intermediate. [76]

Li et al. have found that NAD + directly regulates protein-protein interactions. [77] 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. [77] Thus, the modulation of NAD + may protect against cancer, radiation, and aging. [77]

Extracellular actions of NAD + Edit

In recent years, NAD + has also been recognized as an extracellular signaling molecule involved in cell-to-cell communication. [44] [78] [79] NAD + is released from neurons in blood vessels, [43] urinary bladder, [43] [80] large intestine, [81] [82] from neurosecretory cells, [83] and from brain synaptosomes, [84] and is proposed to be a novel neurotransmitter that transmits information from nerves to effector cells in smooth muscle organs. [81] [82] In plants, the extracellular nicotinamide adenine dinucleotide induces resistance to pathogen infection and the first extracellular NAD receptor has been identified. [85] 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.

The enzymes that make and use NAD + and NADH are important in both pharmacology and the research into future treatments for disease. [86] 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. [87]

Because cancer cells utilize increased glycolysis, and because NAD enhances glycolysis, nicotinamide phosphoribosyltransferase (NAD salvage pathway) is often amplified in cancer cells. [88] [89]

It has been studied for its potential use in the therapy of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. [3] A placebo-controlled clinical trial of NADH (which excluded NADH precursors) in people with Parkinson's failed to show any effect. [90]

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. [91] This radical then reacts with NADH, to produce adducts that are very potent inhibitors of the enzymes enoyl-acyl carrier protein reductase, [92] and dihydrofolate reductase. [93]

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. [94] 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. [94] [95] 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. [96] Compounds such as resveratrol increase the activity of these enzymes, which may be important in their ability to delay aging in both vertebrate, [97] and invertebrate model organisms. [98] [99] In one experiment, mice given NAD for one week had improved nuclear-mitochrondrial communication. [100]

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. [101] [102] 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. [38]

In bacteriology, NAD, sometimes referred to factor V, is used a supplement to culture media for some fastidious bacteria. [103]

The coenzyme NAD + was first discovered by the British biochemists Arthur Harden and William John Young in 1906. [104] 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. [105] 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. [106]

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. [107] Then, in 1939, he provided the first strong evidence that niacin is used to synthesize NAD + . [108] In the early 1940s, Arthur Kornberg was the first to detect an enzyme in the biosynthetic pathway. [109] 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. [110] In 1958, Jack Preiss and Philip Handler discovered the intermediates and enzymes involved in the biosynthesis of NAD + [111] [112] 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 + . [113]

The non-redox roles of NAD(P) were discovered later. [2] The first to be identified was the use of NAD + as the ADP-ribose donor in ADP-ribosylation reactions, observed in the early 1960s. [114] 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. [115]

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. [116] 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). [117] 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. [118]

What is NADH?

So what exactly is NADH?

NADH is the abbreviation for the naturally occurring biological substance, nicotinamide adenine dinucleotide hydride. The “H” stands for high-energy hydrogen and indicates that this substance is in the most biologically active form possible. Often referred to as coenzyme 1, NADH is the body’s top-ranked coenzyme, a facilitator of numerous biological reactions. NADH is necessary for cellular development and energy pro­duction: It is essential to produce energy from food and is the principal carrier of electrons in the energy-producing process in the cells. NADH is also an important antioxidant in fact, scientists acknowledge that NADH is the most powerful antioxidant to protect cells from damage by harmful substances. In summary, NADH is a highly powerful form of vitamin B3 commonly referred to as niacin or niacinamide.

NADH is a coenzyme. What is a coenzyme? A coenzyme is a substance that enhances or is necessary for the action of all enzymes in the body. Coenzymes are generally much smaller molecules than enzymes themselves. Enzymes are large biological molecules that catalyze biological processes and create products in our bodies that we need for basic survival. Without a coenzyme, the majority of enzymes in the body are useless. Enzymes can be compared to production machinery in a factory that transposes one material into another one. In living cells, enzymes catalyze the breakdown and turnover of food components into smaller units, converting food into energy and water. Enzymes can perform their work only if an additional essential factor combines with the molecule itself. This factor is called a coenzyme. Without a complementary coenzyme, enzymes will not work and, therefore, they cannot produce complete protein systems for the human body. Hence, a coenzyme is essential for an enzyme to become active. Unlike DHEA and melatonin, NADH is not a hormone, but a coenzyme.

Why is NADH important? NADH is biologically ranked and identified as coenzyme 1, the coenzyme or cofactor needed for numerous enzymes that are involved in the cellular energy production. A deficiency of NADH will result in an energy deficit at the cellular level, which causes symptoms of fatigue. When the body is deficient in NADH, it is kind of like a car that has run out of gasoline. The more NADH a cell has available, the more energy it can produce. Unfortunately, the production of NADH in our bodies declines as we age, and so does the production of NADH-dependent en­zymes, particularly those enzymes involved in energy production.

Is there a difference between NADH and NADH2? - Biology


The discussion so far in this chapter has dealt with the process of aerobic cellular respiration in eukaryotic organisms. However, some prokaryotic cells also use aerobic cellular respiration. Because prokaryotes do not have mitochondria, there are some differences between what they do and what eukaryotes do. The primary difference involves the electrons carried from glycolysis to the electron-transport system. In eukaryotes, the electrons released during glycolysis are carried by NADH and transferred to FAD to form FADH2 in order to get the electrons across the outer membrane of the mitochondrion. Because FADH2 results in the production of fewer ATPs than NADH, there is a cost to the eukaryotic cell of getting the electrons into the mitochondrion. This transfer is not necessary in prokaryotes, so they are able to produce a theoretical 38 ATPs for each glucose metabolized, rather than the 36 ATPs produced by eukaryotes (table 6.2).

Can anyone explain the difference between NAD, NADH, NADP, NADPH, NADPH2?

Other than the presence of a phosphate, obviously. What is the difference between where each one is used? Is there a NADH2?

NAD is the oxidised form of NADH, both forms are very important in the cell. They play a major role in carrying electrons from one reaction to another and so are used in metabolic reactions. NADH can also be said to act as a store of energy in the sense that energy from catabolic reactions will reduce NAD+ to NADH. NADH can then be taken to a mitochondrion and by oxidized by the electron transport chain, which will generate ATP. The ratio of NAD/NADH in a cell can also have a regulatory effect on the activity of certain enzymes used in metabolic processes.

NADPH is used for reductive biosynthetic pathways and is largely generated by cells during the pentose phosphate pathway. It is used in the production of steroids and fatty acids. NADPH is also important for protection against reactive oxygen species, because of its reducing power.

Animal Models for Disorders of Chronobiology

NAD Biosynthesis and Sirtuins

Nicotinamide adenine dinucleotide (NAD) biosynthesis and the NAD-dependent deacetylase SIRT1 have also emerged at the intersection of the circadian and metabolic pathways. Early studies indicated that the cellular redox status of the cell, represented by the NAD cofactors NAD(H) and NADP(H), regulates the transcriptional activity of CLOCK and its homologue NPAS2. 50 The reduced forms of these cofactors increase, and the oxidized forms decrease, the ability of CLOCK/BMAL1 to bind DNA. Recent studies have further linked the biosynthesis of NAD itself with the core molecular clock. 51 , 52 CLOCK/BMAL1 directly increases expression of the gene encoding the rate-limiting enzyme in NAD biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), in peripheral tissues including liver and white adipose tissue. Both Nampt RNA and NAD levels are reduced in livers from Clock and Bmal1mutant mice and increased in liver from mice lacking both Cry1 and Cry2, suggesting that Nampt, and therefore NAD production, is a direct downstream target of CLOCK/BMAL1. NAD is critical for cellular redox reactions, and it also serves as a substrate for the NAD-dependent and nutrient-responsive deacetylase SIRT1, which in turn negatively regulates the core molecular clock machinery by physically interacting with and inhibiting CLOCK/BMAL1 (see Fig. 40-2 ). 51 , 53

Similar to the nuclear hormone receptor family of proteins, the existence of this pathway linked to the clock is particularly intriguing because NAMPT and SIRT1 are both regulated not only by the clock but also by the nutritional status of the organism. For example, Nampt is upregulated in response to decreased glucose levels in skeletal muscle in a manner dependent on adenosine monophosphate–activated protein kinase (AMPK), 54 , 55 and fasting or caloric restriction elevates SIRT1 levels in multiple tissues. 56-59 NAD and SIRT1 regulate a host of downstream metabolic processes, including glucose-stimulated insulin secretion, adipocyte differentiation, and gluconeogenesis, 60 in addition to regulation of the core clock machinery. Thus, a unifying hypothesis is that the NAMPT-SIRT1-CLOCK/BMAL1 pathway is a metabolic feedback loop that coordinates daily cycles of feeding, fuel use, sleep, and activity.

What is NAD/NADH anyway?

Nicotinamide Adenine Dinucleotide (NAD) is a dinucleotide that functions as one of the most important coenzymes in the cell.

The interconversion of NAD between the reduced (NADH) and oxidized (NAD+) forms is a common reaction in biological redox (oxidation-reduction) reactions. In cells, most oxidations are accomplished by the removal of hydrogen atoms. Each molecule of NAD + can acquire two electrons that is, be reduced by two electrons. However, only one proton accompanies the reduction. The other proton produced as two hydrogen atoms are removed from the molecule being oxidized is liberated into the surrounding medium. For NAD, the reaction is thus:

NAD participates in many redox reactions in cells, including:

The bottom line on glycolysis is that glucose is oxidized to 2 moles of pyruvic acid. The oxidizing agent is NAD+, which is reduced to NADH. The process is exergonic and the mechanism that has evolved allows the energy of reaction to be captured as two moles of ATP per glucose molecule:

2 NAD + + glucose + 2 ADP ------> 2 pyruvate + 2 NADH + 2 ATP


For most tissues in higher organisms, the pyruvate is further oxidized all the way to CO 2 (in the citric acid cycle ). Here, too, the major oxidizing agent is NAD+, although other oxidizing agents are also needed. The citric acid cycle pathway consists of eight reactions that process incoming molecules of Acetyl-CoA. The carbon atoms leave the cycle in the form of molecules of carbon dioxide. The hydrogen atoms and electrons leave the cycle in the form of reduced coenzymes NADH and FADH2. The cycle is regulated by three allosteric enzymes in response to cellular levels of ATP. One Acetyl CoA molecule entering the citric acid cycle produces three molecules of NADH, one of FADH2, and one of GTP. Click here to see the citric acid cycle.


Nicotinamide adenine dinucleotide, NADH, plays a central role in oxidative metabolism . Through the mitochondrial electron transport chain and a series of intermediate redox reactions, NADH can transfer two electrons and a hydrogen ion to molecular oxygen, liberating 52.6 kcal/mole. This is enough energy to synthesize 7.2 ATPs from ADP and Pi. Some inefficiency, though, allows only 3 ATPs to be formed.

For those organisms or tissues that do not carry out aerobic (oxygen-dependent) metabolism, there is the problem of re-generating the oxidizing agent NAD+. For mammalian tissues such as muscle and red blood cells, and for some microorganisms such as lactic acid bacteria, the NADH is used to reduce pyruvate to lactate.

For other microorganisms the pyruvate can be further oxidized to acetaldehyde which can then be reduced by NADH to a number of different products depending on the particular organism. Ethanol-producing yeast and bacteria, reduce acetaldehyde:

For mammals, the acetaldehyde, which is very toxic, must be further oxidized to acetic acid.

Structure and Function of Various Coenzymes (With Diagram)

Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are derivatives of the B-vitamin, nicotinic acid.

The structures are shown in Fig. 8.30:

NAD and NADP act as conezymes for many degydrogenases where they are involved in transfer of hydrogen, causing either oxidation or reduction of the substrates. In general, NAD takes part in the catabolic reactions, which NADP in synthetic pathway reactions. Some NAD containing dehydrogenases are lactic dehydrogenase, alcohol dehydrogenase, malate dehydrogenase, glycerin aldehyde phosphate dehydrogenase etc.

Two examples are cited below, one of reduction and the other or oxidation:

Lactic acid is oxidized to pyruvic acid where NAD acts as H-acceptor. In the other reaction, acetaldehyde is reduced to ethanol where NADH2 acts as H-donor.

Example of NADP catalysed reacted are glucose 6-phosphate dehydrogenase, isocitrate dehydrogenase, glutamic acid dehydrogenase etc.:

Although the reduced forms of NAD and NADP are usually shown as NADH2 and NADPH2 for convenience, it should be noted that the correct forms should be NADH+H + and NADPH+H + respectively, because the positively charged nicotinamide ring accepts one electron and one H-atom from a pair of H-atoms removed from the substrate. The electron goes to the positively charged N-atom and another hydrogen is added at the position shown in Fig. 8.30.

NAD and NADP were previously called DPN (diphosphopyridine nucleotide) and TPN (triphospho pyridine nucleotide), respectively.

2. Flavin Mononucleotide (FMN) and Flavin Adenine Dinucleotide (FAD):

FMN and FAD, commonly called flavoproteins, are also hydrogen transferring coenzymes associated with hydrogenases. The coenzyme parts of these flavoproteins contain the B-vitamin, riboflavin. In contrast to NAD or NADP, the coenzymes of flavoproteins are more tightly bound to the apoenzyme. As a result they cannot be separated by dialysis.

The structures of riboflavin, FMN and FAD are shown in Fig. 8.31:

On reduction of FAD by addition of two H-atoms donated by a substrate, it is converted to FADH2. The H-accepting positions are shown in Fig. 8.32. The substrate is thereby oxidized. An example of FAD containing enzyme is succinate dehydrogenase occurring in the Krebs’ cycle. Succinic acid is oxidized to fumaric acid by the enzyme. The hydrogen accepted by FAD is transferred to the electron transport chain for generation of ATP.

3. Coenzyme A (CoA):

Coenzyme A has a complex structure consisting of an adenosine triphosphate, a pantothenic acid which is a B-vitamin and cysteamine. The coenzyme is involved in transfer of acyl-groups. The sulfhydryl (-SH) group of cysteamine moiety of this coenzyme forms a thioester with the carboxyl (-COOH) group of the acyl-compound, such as acetic acid to produce acetyl-CoA which is one of the most important CoA derivatives. The thioester bond is energy-rich and can easily transfer the acetyl- group to an acceptor.

The structure of coenzyme A, formation of a thioester and a reaction involving coenzyme A are shown in Fig. 8.33:

4. Thiamine Pyrophosphate (TPP):

TPP is a coenzyme involved in transfer of aldehyde (—C—H) groups, like acetaldehyde and glycol aldehyde. It contains thiamine, a vitamin of B-group. The thiazole group of the coenzyme molecule accepts the aldehyde group and transfers it to an acceptor via other coenzymes, like lipoic acid and coenzyme A. TPP is involved in oxidative decarboxylation of pyruvic acid and α-ketoglutaric acid.

The structures of TPP and ‘active’ acetaldehyde are shown in Fig. 8.34:

An example of an enzyme complex involving TPP, lipoic acid and coenzyme A is the pyruvate decarboxylase.

The reaction is shown in a simplified way (Fig. 8.35):

5. Pyridoxal Phosphate (PAL):

Pyridoxal phosphate is a coenzyme associated with — transaminases which catalyse transfer of amino groups from amino acids to keto acids. In this transfer process, PAL acts as the acceptor of the amino group and is converted to pyridoxamine phosphate (PAM).

PAM can react with a keto acid to produce an amino acid. PAL and PAM remain bound to the protein part of the transaminase enzyme during these transfer of amino group. The reactions catalysed by transaminases can be represented in a simple way as shown in Fig. 8.36. Pyridoxal phosphate has a simple molecule containing the B-vitamin, pyridoxine.

The structures of PAL and PAM are shown in Fig. 8.36:

The aldehyde group of PAL is the reactive group of the coenzyme which binds to the amino acid forming a Schiff s base.

The details of transaminase reaction are shown in Fig. 8.37:

6. Other Molecules having Coenzyme Function:

These include lipoic acid (thioctic acid), biotin, tetrahydrofolic acid and cobalamine.

The structures of some of these compounds are shown in Fig. 8.38:

Lipoic acid is involved in oxidative decarboxylation reactions, such as those catalysed by pyruvic decarboxylase or α-keto glutarate decarboxylase. Biotin is bound to enzymes involved in carboxylation reactions. In such reactions biotin acts as the carrier of CO2. The CO2-biotin compound is known as active CO2. An example is pyruvate carboxylase which adds a CO2 molecule to pyruvic acid forming oxalacetic acid.

Tetrahydrofolic acid (THF) acts as coenzyme for enzymes involved in transfer of one-carbon fragments, like formyl, methyl and methenyl groups. An example of a reaction involving THF is conversion of homocysteine to methionine. The methyl group of methionine is added from methyl-THF. Another THF mediated reaction is conversion of serine to glycine where the hydroxy-methyl group of serine is removed by THF.

Cobalamine or vitamin B12 is a cobalt-containing complex molecule composed of 63 carbon atoms, a tetrapyrole ring system and a nucleotide. The cobalt atom is held in the tetrapyrole ring and carries a cyano (-CN) group. Cobalamine acts as coenzyme for enzymes catalyzing intra-molecular transfer of carboxyl group. An important reaction of this type is conversion of methyl malonyl- coenzyme A to succinyl-coenzyme A.


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