Because of the linkage of the vitamin nicotinamide to the ring of the sugar ribose, NAD+ and its relative NADP+ (which carries an extra phospho group in its structure; Fig. 8) can be reduced by transfer of a hydrogen atom from an alcohol or other suitable substrate to the 4 position of the ring. As illustrated in Fig. 8, the transfer is that of a hydrogen atom plus an electron (a hydride ion H−). NAD+ plays this role in many biological dehydrogenation reactions which convert various alcohols into the corresponding carbonyl compounds—aldehydes or ketones. At the same time, many carbonyl compounds are reduced to alcohols. Sometimes the oxidation and reduction processes are linked. A well-known example is the oxidation of glyceraldehyde 3-phosphate during the breakdown of glucose,aprocess that occurs inbacteria, yeast, andthehuman body. In all cases NAD+ is reduced to NADH + H+. The latter is reoxidized to NAD+ in the human body, but in lactic acid bacteria the NADH is used (always together with an H+ ion) to reduce pyruvic acid to lactic acid. This provides a balanced fermentation process that requires no oxygen. Under conditions of extreme exertion, e.g., in a 100-meter race, the lactic acid fermentation fuels human muscles. In yeast, a similar fermentation reduces acetaldehyde to ethanol, indirectly providing energy for the cell.
Why are there two similar coenzymes NAD and NADP? A generalization that holds in many instances is that NAD+ initiates dehydrogenation (oxidation) while NADPH acts as a biological reductant. This permits oxidative pathways utilizing NAD+ to occur at the same time as reductive processes that utilize NADPH. Cells of aerobic organisms often keep the concentration ratio of the reactants [NAD+]/[NADH] high at the same time that the ratio [NADPH] / [NADP+] is also high. Nicotinamide is a very stable compound, but the coenzyme forms are surprisingly easily destroyed. The reduced forms NADH and NADPH are extremely unstable below pH 7, undergoing ring opening reactions. NAD+ and NADP+ are unstable at high pH, hydroxide ions adding to double bonds in the nicotinamide ring with subsequent destruction of the coenzymes. It is not surprising that our bodies need a daily supply of this vitamin.
Like NAD+, FAD and the simpler riboflavin monophosphate (FMN) often serve as an acceptor of a hydride (H−) ion. However, FAD is a more powerful oxidant than is NAD+. This fact is indicated in a quantitative way by the standard reduction potential, which biochemists tabulate for pH 7. At this pH the standard hydrogen electrode potential E0´ (for the couple H+/H2) is −0.414 V while that for the powerful oxidant O2 (O2/H2O) is +0.815 at 25°C. For the NAD+/NADH couple E0´ is −0.32 V and for FAD/FADH2 it is −0.21 V. However, since FAD and FADH2 are often tightly bound as flavoproteins, the value of E0´ for flavoproteins varies over a broad range from −0.49 to +0.19 V. The value depends upon the relative strength of binding of the oxidized and reduced forms of FAD to the specific catalytic proteins. In the β oxidation of fatty acids (Fig. 12), the powerful oxidizing properties of FAD make it possible to remove a C3 hydrogen atom as H− either after or concurrently with the removal of a proton from C2. The latter requires participation of a basic group from the protein as well as activation by the CoA thioester group (step b in Fig. 12). The thioester group also facilitates addition of an HO− ion at the C3 position in step c to form an alcohol. The latter is dehydrogenated by NAD+ in step d.
Another important aspect of FAD chemistry is the ability to accept a single hydrogen atom (or a single electron together with a proton) to form a free radical, which we may designate FADH•; the dot indicates the reactive unpaired electron. This ability allows FAD or FMN to accept a hydride ion, undergoing a two-electron reduction, then pass the electrons one at a time to an electron-accepting metal center in an electron transport chain such as that found in membranes of the mitochondria. It is at the ends of these electron transport chains that oxygen (O2), brought into the human body through the lungs, combines with four electrons and four protons to form two water molecules. At the other end of the chain −OH groups in a variety of metabolic intermediates are dehydrogenated to carbonyl groups by molecules of NAD+. The resulting NADH transfers its hydrogen (plus a free H+) to FMN within the mitochondrial chain. These reactions, which pass electrons through the electron transport chain, account for most of the oxygen utilized in respiration.
The ability to accept single electrons also allows FAD or FMN attached to some enzyme proteins to react directly with O2, reducing the O2 to hydrogen peroxide, H2O2. The latter has useful functions within cells but may also cause damage. Molecular oxygen (O2) combined chemically with the reduced riboflavin is also used by hydroxylases of bacteria and plants to introduce −OH groups into a variety of compounds. A peroxide form of FMN, when bound to the correct protein of luminous bacteria, emits visible light.
Living cells contain many other hydrogen and electron carriers. Among them are lipoic acid (Fig. 11), quinones such as vitamin K, ubiquinone and plastoquinone (Fig. 3), and metal centers containing iron, copper, nickel, manganese, and cobalt.
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