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Riboflavin and Old Yellow Enzyme

Riboflavin was first isolated from whey in 1879 by Blyth, and the structure was determined by Kuhn and coworkers in 1933. For the structure determination, this group isolated 30 mg of pure riboflavin from the whites of about 10,000 eggs. The discovery of the actions of riboflavin in biological systems arose from the work of Otto Warburg in Germany and Hugo Theorell in Sweden, both of whom identified yellow substances bound to a yeast enzyme involved in the oxidation of pyridine nucleotides. Theorell showed that riboflavin 5'-phosphate was the source of the yellow color in this old yellow enzyme. By 1938, Warburg had identified FAD, the second common form of riboflavin, as the coenzyme in D-amino acid oxidase, another yellow protein. Riboflavin deficiencies are not at all common. Humans require only about 2 mg per day, and the vitamin is prevalent in many foods. This vitamin is extremely light sensitive, and it is degraded in foods (milk, for example) left in the sun.

The milling and refining of wheat, rice, and other grains causes a loss of riboflavin and other vitamins. In order to correct and prevent dietary deficiencies, the Committee on Food and Nutrition of the National Research Council began in the 1940s to recommend enrichment of cereal grains sold in the United States. Thiamine, riboflavin, niacin, and iron were the first nutrients originally recommended for enrichment by this group. As a result of these actions, generations of American children have become accustomed to reading (on their cereal boxes and bread wrappers) that their foods contain certain percentages of the "U.S. Recommended Daily Allowance" of various vitamins and nutrients.

FIGURE 18.23 • The structure of coenzyme A. Acyl groups form thioester linkages with the —SH group of the ^-mercaptoethylamine moiety.

Pantothenic Acid and Coenzyme A

Pantothenic acid, sometimes called vitamin B3, is a vitamin that makes up one part of a complex coenzyme called coenzyme A (CoA) (Figure 18.23). Pantothenic acid is also a constituent of acyl carrier proteins. Coenzyme A consists of 3',5'-adenosine bisphosphate joined to 4-phosphopantetheine in a phosphoric anhydride linkage. Phosphopantetheine in turn consists of three parts: ¡-mercaptoethylamine linked to ¡-alanine, which makes an amide bond with a branched-chain dihydroxy acid. As was the case for the nicotinamide and flavin coenzymes, the adenine nucleotide moiety of CoA acts as a recognition site, increasing the affinity and specificity of CoA binding to its enzymes.

The two main functions of coenzyme A are

(a) activation of acyl groups for transfer by nucleophilic attack and

(b) activation of the a-hydrogen of the acyl group for abstraction as a proton. Both of these functions are mediated by the reactive sulfhydryl group on CoA, which forms thioester linkages with acyl groups.

The activation of acyl groups for transfer by CoA can be appreciated by comparing the hydrolysis of the thioester bond of acetyl-CoA with hydrolysis of a simple oxygen ester:

Ethyl acetate Acetyl-SCoA

h2o acetate + ethanol + H+ aG° -> acetate + CoA-SH + H+ AGC

Hydrolysis of the thioester is more favorable than that of oxygen esters, presumably because the carbon-sulfur bond has less double bond character than the corresponding carbon-oxygen bond. This means that transfer of the acetyl group from acetyl-CoA to a given nucleophile (Figure 18.24) will be more spontaneous than transfer of an acetyl group from an oxygen ester. For this reason, acetyl-CoA is said to have a high group-transfer potential.

The 4-phosphopantetheine group of CoA is also utilized (for essentially the same purposes) in acyl carrier proteins (ACPs) involved in fatty acid biosynthesis (see Chapter 25). In acyl carrier proteins, the 4-phosphopantetheine is covalently linked to a serine hydroxyl group. Pantothenic acid is an essential factor for the metabolism of fat, protein, and carbohydrates in the tricarboxylic acid cycle and other pathways. In view of its universal importance in metabolism, it is surprising that pantothenic acid deficiencies are not a more serious problem in humans, but this vitamin is abundant in almost all foods, so that deficiencies are rarely observed.

^-Mercaptoethylamine

Pantothenic acid

^-Mercaptoethylamine

Pantothenic acid

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