Amino Acids Are Precursors of Many Biomolecules

III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.3. Amino Acid Biosynthesis Is Regulated by Feedback Inhibition
Figure 24.27. Structure of the Regulatory Protein P. This trimeric regulatory protein controls the modification of
glutamine synthetase.
III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.3. Amino Acid Biosynthesis Is Regulated by Feedback Inhibition
Figure 24.28. A Higher Level in the Regulatory Cascade of Glutamine Synthetase. PA and PD, the regulatory
proteins that control the specificity of adenylyl transferase, are interconvertible. PA is converted into PD by uridylylation,
which is reversed by hydrolysis. The enzymes catalyzing these reactions are regulated by the concentrations of metabolic
intermediates.
III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.4. Amino 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).
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.
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 (ESe-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).
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.
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).
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.
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 enzymebound 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).
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.
24.4.4. Porphyrins Accumulate in Some Inherited Disorders of Porphyrin Metabolism
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.
III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.4. Amino Acids Are Precursors of Many Biomolecules
Figure 24.29. Selected Biomolecules Derived from Amino Acids. The atoms contributed by amino acids are shown in
blue.
III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.4. Amino Acids Are Precursors of Many Biomolecules
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.
III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.4. Amino Acids Are Precursors of Many Biomolecules
Figure 24.31. Structure of Glutathione Peroxidase. This enzyme, which has a role in peroxide detoxification, contains
a selenocysteine residue in its active site.
III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.4. Amino Acids Are Precursors of Many Biomolecules
Figure 24.32. Catalytic Cycle of Glutathione Peroxidase. [After O. Epp, R. Ladenstein, and A. Wendel. Eur. J.
Biochem. 133(1983):51.]
III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.4. Amino Acids Are Precursors of Many Biomolecules
Figure 24.33. Formation of Nitric Oxide. NO is generated by the oxidation of arginine.
III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.4. Amino Acids Are Precursors of Many Biomolecules
Figure 24.34. Heme Labeling. The origins of atoms in heme revealed by the results of isotopic labeling studies.
III. Synthesizing the Molecules of Life
24. The Biosynthesis of Amino Acids
24.4. Amino Acids Are Precursors of Many Biomolecules