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Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.

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Biochemistry. 5th edition.

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Section 24.4Amino Acids Are Precursors of Many Biomolecules

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 24.29).

Figure 24.29. Selected Biomolecules Derived from Amino Acids.

Figure 24.29

Selected Biomolecules Derived from Amino Acids. The atoms contributed by amino acids are shown in blue.

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 the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. 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.

24.4.1. Glutathione, a Gamma-Glutamyl Peptide, Serves as a Sulfhydryl Buffer and an Antioxidant

Glutathione, a tripeptide containing a sulfhydryl group, is a highly distinctive amino acid derivative with several important roles (Figure 24.30). For example, glutathione, present at high levels (≈5 mM) in animal cells, protects red cells from oxidative damage by serving as a sulfhydryl buffer (Section 20.5.1). 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.

Image ch24fu18.jpg

Figure 24.30. Glutathione.

Figure 24.30

Glutathione. This tripeptide consists of a cysteine residue flanked by a glycine residue and a glutamate residue that is linked to cysteine by an isopeptide bond between glutamate's side-chain carboxylate group and cysteine's amino group.

Glutathione peroxidase, the enzyme catalyzing this reaction, is remarkable in having a modified amino acid containing a selenium (Se) atom (Figure 24.31). 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 24.32).

Figure 24.31. Structure of Glutathione Peroxidase.

Figure 24.31

Structure of Glutathione Peroxidase. Image mouse.jpg This enzyme, which has a role in peroxide detoxification, contains a selenocysteine residue in its active site.

Figure 24.32. Catalytic Cycle of Glutathione Peroxidase.

Figure 24.32

Catalytic Cycle of Glutathione Peroxidase. [After O. Epp, R. Ladenstein, and A. Wendel. Eur. J. Biochem. 133(1983):51.]

24.4.2. Nitric Oxide, a Short-Lived Signal Molecule, Is Formed from Arginine

Nitric oxide (NO) is an important messenger in many vertebrate signal-transduction processes. 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 24.33). Nitric oxide acts by binding to and activating soluble guanylate cyclase, an important enzyme in signal transduction (Section 32.3.3). This enzyme is homologous to adenylate cyclase but includes a heme-containing domain that binds NO.

Figure 24.33. Formation of Nitric Oxide.

Figure 24.33

Formation of Nitric Oxide. NO is generated by the oxidation of arginine.

24.4.3. Mammalian Porphyrins Are Synthesized from Glycine and Succinyl Coenzyme A

The involvement of an amino acid in the biosynthesis of the porphyrin rings of hemes and chlorophylls was first revealed by the results of isotopiclabeling 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 (of whom Shemin was the first), whereas the ingestion of [15N]glutamate resulted in very little labeling.

15N labeling: A pioneer's account—

"Myself as a Guinea Pig

“… in 1944, I undertook, together with David Rittenberg, an investigation on the turnover of blood proteins of man. To this end I synthesized 66 g of glycine labeled with 35 percent 15N at a cost of $1000 for the 15N. On 12 February 1945, I started the ingestion of the labeled glycine. Since we did not know the effect of relatively large doses of the stable isotope of nitrogen and since we believed that the maximum incorporation into the proteins could be achieved by the administration of glycine in some continual manner, I ingested 1 g samples of glycine at hourly intervals for the next 66 hours…. At stated intervals, blood was withdrawn and after proper preparation the 15N concentrations of different blood proteins were determined.”

-David Shemin

Bioessays 10(1989):30

Using 14C, which had just become available, they discovered 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. The results of 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 carbons, whereas the 14C in carboxyl-labeled acetate appeared only in the other 2 (Figure 24.34).

Figure 24.34. Heme Labeling.

Figure 24.34

Heme Labeling. The origins of atoms in heme revealed by the results of isotopic labeling studies.

This highly distinctive labeling pattern led Shemin to propose that a heme precursor is formed by the condensation of glycine with an activated succinyl compound. In fact, the first step in the biosynthesis of porphyrins in mammals is the condensation of glycine and succinyl CoA to form δ-aminolevulinate.

Image ch24fu19.jpg

This reaction is catalyzed by δ-aminolevulinate synthase, a PLP enzyme present in mitochondria. 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 nonphysiologic 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 24.35).

Figure 24.35. Heme Biosynthetic Pathway.

Figure 24.35

Heme Biosynthetic Pathway. The pathway for the formation of heme starts with eight molecules of δ-aminolevulinate.

The porphyrin skeleton is now formed. Subsequent reactions alter the side chains and the degree of saturation of the porphyrin ring (see Figure 24.34). 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 stored in tissues inside molecules of ferritin. The large internal cavity (≈ 80 Å in diameter) of ferritin can hold as many as 4500 ferric ions (Section 31.4.2).

The normal human erythrocyte has a life span of about 120 days, as was first shown by the time course of 15N in Shemin's own hemoglobin after he ingested 15N-labeled glycine. The first step in the degradation of the heme group is the cleavage of its α-methene bridge to form the green pigment biliverdin, a linear tetrapyrrole. The central methene bridge of biliverdin is then reduced by biliverdin reductase to form bilirubin, a red pigment (Figure 24.36). The changing color of a bruise is a highly graphic indicator of these degradative reactions.

Figure 24.36. Heme Degradation.

Figure 24.36

Heme Degradation. The formation of the heme-degradation products biliverdin and bilirubin is responsible for the color of bruises. Abbreviations: M, methyl; V, vinyl.

24.4.4. Porphyrins Accumulate in Some Inherited Disorders of Porphyrin Metabolism

Image caduceus.jpg 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 eythrocytes. 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 photoexcited 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, is believed to have been due to this porphyria.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, W. H. Freeman and Company.
Bookshelf ID: NBK22446

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