In addition to being the building blocks of proteins and peptides, amino acids serve as precursors of many kinds of small molecules that have important and diverse biological roles. Let us briefly survey some of the biomolecules that are derived from amino acids (Figure 24.22).

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of thyroxine (tetraiodothyronine, a hormone that modulates metabolism), epinephrine (adrenaline), and melanin (a complex polymeric molecule responsible for skin pigmentation). The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD⁺ are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids.

Glutathione, a tripeptide containing a sulfhydryl group, is a highly distinctive amino acid derivative with several important roles (Figure 24.23). For example, glutathione, present at high levels (∼5 mM) in animal cells, protects red blood cells from oxidative damage by serving as a sulfhydryl buffer (Section 20.5). It cycles between a reduced thiol form (GSH) and an oxidized form (GSSG) in which two tripeptides are linked by a disulfide bond.

GSSG is reduced to GSH by glutathione reductase, a flavoprotein that uses NADPH as the electron source. The ratio of GSH to GSSG in most cells is greater than 500. Glutathione plays a key role in detoxification by reacting with hydrogen peroxide and organic peroxides, the harmful by-products of aerobic life.

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Glutathione peroxidase, the enzyme catalyzing this reaction, is remarkable in having a modified amino acid containing a selenium (Se) atom (Figure 24.24). Specifically, its active site contains the selenium analog of cysteine, in which selenium has replaced sulfur. The selenolate (E-Se⁻) form of this residue reduces the peroxide substrate to an alcohol and is in turn oxidized to selenenic acid (E-SeOH). Glutathione then comes into action by forming a selenosulfide adduct (E-Se-S-G). A second molecule of glutathione then regenerates the active form of the enzyme by attacking the selenosulfide to form oxidized glutathione (Figure 24.25).

Nitric oxide (NO) is an important messenger in many vertebrate signal-transduction processes, identified first as a relaxing factor in the cardiovascular system. It is now known to have a variety of roles not only in the cardiovascular system, but also in the immune and nervous systems. NO has also been shown to stimulate mitochondrial biogenesis. This free-radical gas is produced endogenously from arginine in a complex reaction that is catalyzed by nitric oxide synthase. NADPH and O₂ are required for the synthesis of nitric oxide (Figure 24.26). Nitric oxide acts by binding to and activating soluble guanylate cyclase, an important enzyme in signal transduction (Section 32.3). This enzyme is homologous to adenylate cyclase but includes a heme-containing domain that binds NO.

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The participation of an amino acid in the biosynthesis of the porphyrin rings of hemes and chlorophylls was first revealed by isotope-labeling experiments carried out by David Shemin and his colleagues. In 1945, they showed that the nitrogen atoms of heme were labeled after the feeding of [¹⁵N]glycine to human subjects, whereas the ingestion of [¹⁵N]glutamate resulted in very little labeling.

Experiments using ¹⁴C, which had just become available, revealed that 8 of the carbon atoms of heme in nucleated duck erythrocytes are derived from the α-carbon atom of glycine and none from the carboxyl carbon atom. Subsequent studies demonstrated that the other 26 carbon atoms of heme can arise from acetate. Moreover, the ¹⁴C in methyl-labeled acetate emerged in 24 of these carbon atoms, whereas the ¹⁴C in carboxyl-labeled acetate appeared only in the other 2 (Figure 24.27).

This highly distinctive labeling pattern suggested that acetate is converted to succinyl-CoA through enzymes from the citric acid cycle (Section 17.2) and that a heme precursor is formed by the condensation of glycine with succinyl-CoA. Indeed, the first step in the biosynthesis of porphyrins in mammals is the condensation of glycine and succinyl CoA to form δ-aminolevulinate.

This reaction is catalyzed by δ-aminolevulinate synthase, a PLP enzyme present in mitochondria. Consistent with the labeling studies described earlier, the carbon atom from the carboxyl group of glycine is lost as carbon dioxide, while the α-carbon remains in δ-aminolevulinate.

Two molecules of δ-aminolevulinate condense to form porphobilinogen, the next intermediate. Four molecules of porphobilinogen then condense head to tail to form a linear tetrapyrrole in a reaction catalyzed by porphobilinogen deaminase. The enzyme-bound linear tetrapyrrole then cyclizes to form uroporphyrinogen III, which has an asymmetric arrangement of side chains. This reaction requires a cosynthase. In the presence of synthase alone, uroporphyrinogen I, the nonphysiological symmetric isomer, is produced. Uroporphyrinogen III is also a key intermediate in the synthesis of vitamin B₁₂ by bacteria and that of chlorophyll by bacteria and plants (Figure 24.28).

The porphyrin skeleton is now formed. Subsequent reactions alter the side chains and the degree of saturation of the porphyrin ring (Figure 24.28). Coproporphyrinogen III is formed by the decarboxylation of the acetate side chains. The desaturation of the porphyrin ring and the conversion of two of the propionate side chains into vinyl groups yield protoporphyrin IX. The chelation of iron finally gives heme, the prosthetic group of proteins such as myoglobin, hemoglobin, catalase, peroxidase, and cytochrome c. The insertion of the ferrous form of iron is catalyzed by ferrochelatase. Iron is transported in the plasma by transferrin, a protein that binds two ferric ions, and is stored in tissues inside molecules of ferritin (Section 32.4).

Studies with ¹⁵N-labeled glycine revealed that the normal human erythrocyte has a life span of about 120 days. The first step in the degradation of the heme group is the cleavage of its α-methine bridge to form the green pigment biliverdin, a linear tetrapyrrole. The central methine bridge of biliverdin is then reduced by biliverdin reductase to form bilirubin, a red pigment (Figure 24.29). The changing color of a bruise is a highly graphic indicator of these degradative reactions.

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Porphyrias are inherited or acquired disorders caused by a deficiency of enzymes in the heme biosynthetic pathway. Porphyrin is synthesized in both the erythroblasts and the liver, and either one may be the site of a disorder. Congenital erythropoietic porphyria, for example, prematurely destroys erythrocytes. This disease results from insufficient cosynthase. In this porphyria, the synthesis of the required amount of uroporphyrinogen III is accompanied by the formation of very large quantities of uroporphyrinogen I, the useless symmetric isomer. Uroporphyrin I, coproporphyrin I, and other symmetric derivatives also accumulate. The urine of patients having this disease is red because of the excretion of large amounts of uroporphyrin I. Their teeth exhibit a strong red fluorescence under ultraviolet light because of the deposition of porphyrins. Furthermore, their skin is usually very sensitive to light because photoex-cited porphyrins are quite reactive. Acute intermittent porphyria is the most prevalent of the porphyrias affecting the liver. This porphyria is characterized by the overproduction of porphobilinogen and δ-aminolevulinate, which results in severe abdominal pain and neurological dysfunction. The “madness” of George III, king of England during the American Revolution, may have been due to this porphyria.

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