Some enzymes may require the help of some other small molecule or ion to catalyze a reaction. The molecules that are bound to enzymes for this purpose are called coenzymes. Like enzymes, coenzymes are not irreversibly changed during catalysis; they are either unmodified or regenerated. Each kind of coenzyme has a particular chemical function. Some are oxidation/reduction agents, some facilitate group transfers, and so forth. In fact, if we consider electrons as "groups" to transfer, we can categorize all coenzymes as being involved in transfer processes. The number of important coenzymes is limited, but each of them may be associated with many different enzymes.

Sometimes it is difficult to make a clear distinction between a true coenzyme and a second substrate in a reaction. The dehydrogenase enzymes, such as alcohol dehydrogenase, each have a strong binding site for NAD⁺, the oxidized form. After oxidation of the substrate, NADH, the reduced form, leaves the enzyme and is reoxidized by other electron-acceptor systems in the cells. The NAD⁺ so formed can bind to another enzyme molecule and repeat the cycle. In such cases, NAD⁺ acts more like a second substrate than a true coenzyme. Nevertheless, NAD⁺ and NADH differ from most substrates in that they are continually recycled in the cell and are used over and over again. Because of this behavior, NAD⁺ and NADH are considered to be coenzymes.

NAD⁺ behaves unambiguously as a coenzyme in the UDP-glucose 4-epimerase reaction shown in Figure 11.26. This enzyme facilitates synthesis of complex polysaccharides by interconverting UDP-glucose and UDP-galactose. The mechanism by which the hydroxyl at position 4 is changed in stereochemical orientation involves oxidation of the hydroxyl to a carbonyl as an intermediate state. In this case, NAD⁺ and NADH never leave the enzyme; they are reduced and reoxidized in a cyclic fashion, providing a temporary resting place for electrons and the hydrogen from the substrate. This reaction provides a good example of what coenzymes do and why they are necessary. The carbonyl intermediate provides an excellent intermediate state for interconversion of the sugars, but none of the normal amino acid side chains of a protein are really well suited to promote this kind of oxidation and reduction. By binding NAD⁺, the enzyme can carry out this function. Examples of reaction types that require different coenzymes are included in Table 11.5.

Many of the coenzymes are closely related to vitamins, as Table 11.5 shows. In the table, the portion of the coenzyme molecule that must be provided in the human diet as a vitamin is identified in blue. Keep in mind, though, that other vitamins (such as vitamin A for example) play essential physiological roles but are not associated with coenzymes.