8.6.1. Water-Soluble Vitamins Function As Coenzymes

Table 8.9 lists the water-soluble vitamins—ascorbic acid (vitamin C) and a series known as the vitamin B complex (Figure 8.32). Ascorbate, the ionized form of ascorbic acid, serves as a reducing agent (an antioxidant), as will be discussed shortly. The vitamin B series comprises components of coenzymes. Note that, in all cases except vitamin C, the vitamin must be modified before it can serve its function.

Figure 8.32

Structures of Some Water-Soluble Vitamins.

Vitamin deficiencies are capable of causing a variety of pathological conditions (see Table 8.9). However, many of the same symptoms can result from conditions other than lack of a vitamin. For this reason and because vitamins are required in relatively small amounts, pathological conditions resulting from vitamin deficiencies are often difficult to diagnose.

The requirement for vitamin C proved relatively straightforward to demonstrate. This water-soluble vitamin is not used as a coenzyme but is still required for the continued activity of proyl hydroxylase. This enzyme synthesizes 4-hydroxyproline, an amino acid that is required in collagen, the major connective tissue in vertebrates, but is rarely found anywhere else. How is this unusual amino acid formed and what is its role? The results of radioactive-labeling studies showed that proline residues on the amino side of glycine residues in nascent collagen chains become hydroxylated. The oxygen atom that becomes attached to C-4 of proline comes from molecular oxygen, O₂. The other oxygen atom of O₂ is taken up by α-ketoglutarate, which is converted into succinate (Figure 8.33). This complex reaction is catalyzed by prolyl hydroxylase, a dioxygenase. It is assisted by an Fe²⁺ ion, which is tightly bound to it and needed to activate O₂. The enzyme also converts α-ketoglutarate into succinate without hydroxylating proline. In this partial reaction, an oxidized iron complex is formed, which inactivates the enzyme. How is the active enzyme regenerated? Ascorbate (vitamin C) comes to the rescue by reducing the ferric ion of the inactivated enzyme. In the recovery process, ascorbate is oxidized to dehydroascorbic acid (Figure 8.34). Thus, ascorbate serves here as a specific antioxidant.

Figure 8.33

Formation of 4-Hydroxyproline. Proline is hydroxylated at C-4 by the action of prolyl hydroxylase, an enzyme that activates molecular oxygen.

Figure 8.34

Forms of Ascorbic Acid (Vitamin C). Ascorbate is the ionized form of vitamin C, and dehydroascorbic acid is the oxidized form of ascorbate.

Primates are unable to synthesize ascorbic acid and hence must acquire it from their diets. The importance of ascorbate becomes strikingly evident in scurvy. Jacques Cartier in 1536 gave a vivid description of this dietary deficiency disease, which afflicted his men as they were exploring the Saint Lawrence River:

Some did lose all their strength, and could not stand on their feet. … Others also had all their skins spotted with spots of blood of a purple colour: then did it ascend up to their ankles, knees, thighs, shoulders, arms, and necks. Their mouths became stinking, their gums so rotten, that all the flesh did fall off, even to the roots of the teeth, which did also almost all fall out.

James Lind, a Scottish physician, illuminated the means of preventing scurvy in an article titled “A Treatise of the Scurvy” published in 1747. Lind described a controlled study establishing that scurvy could be prevented by including citrus fruits in the diet. The Royal Navy eventually began issuing lime rations to sailors, from which custom British sailors acquired the nickname “limeys.” Lind's research was inspired by the plight of an expedition commanded by Commodore George Anson. Anson left England in 1740 with a fleet of six ships and more than 1000 men and returned with an enormous amount of treasure, but of his crew only 145 survived to reach home. The remainder had died of scurvy.

Why does impaired hydroxylation have such devastating consequences? Collagen synthesized in the absence of ascorbate is less stable than the normal protein. Studies of the thermal stability of synthetic polypeptides have been especially informative. Hydroxyproline stabilizes the collagen triple helix by forming interstrand hydrogen bonds. The abnormal fibers formed by insufficiently hydroxylated collagen contribute to the skin lesions and blood-vessel fragility seen in scurvy.

8.6.2. Fat-Soluble Vitamins Participate in Diverse Processes Such as Blood Clotting and Vision

Not all vitamins function as coenzymes. The fat-soluble vitamins, which are designated by the letters A, D, E, and K (Figure 8.35, Table 8.10), have a diverse array of functions. Vitamin K, which is required for normal blood clotting (K from the German koagulation), participates in the carboxylation of glutamate residues to γ-carboxyglutamate, which makes modified glutamic acid a much stronger chelator of Ca²⁺ (Section 10.5.7). Vitamin A (retinol) is the precursor of retinal, the light-sensitive group in rhodopsin and other visual pigments (Section 32.3.1). A deficiency of this vitamin leads to night blindness. In addition, young animals require vitamin A for growth. Retinoic acid, which contains a terminal carboxylate in place of the alcohol terminus of retinol, serves as a signal molecule and activates the transcription of specific genes that mediate growth and development (Section 31.3). A metabolite of vitamin D is a hormone that regulates the metabolism of calcium and phosphorus. A deficiency in vitamin D impairs bone formation in growing animals. Infertility in rats is a consequence of vitamin E (α-tocopherol) deficiency. This vitamin reacts with and neutralizes reactive oxygen species such as hydroxyl, radicals before they can oxidize unsaturated membrane lipids, damaging cell structures.

Figure 8.35

Structures of Some Fat-Soluble Vitamins.