CHAPTER 3 - Amino Acids &amp Amp Peptides

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CHAPTER 3: Amino Acids & Peptides
Peter J. Kennelly; Victor W. Rodwell
INTRODUCTION
OBJECTIVES
After studying this chapter, you should be able to:
Diagram the structures and write the three and oneletter designations for each of the amino acids present in proteins.
Describe the contribution of each type of R group of the protein amino acids to their chemical properties.
List additional key functions of amino acids and explain how certain amino acids in plant seeds can severely impact human health.
Name the ionizable groups of the protein amino acids and list their approximate pKa values as free amino acids in aqueous solution.
Calculate the pH of an unbuffered aqueous solution of a polyfunctional amino acid and the change in pH that occurs following the addition of a
given quantity of strong acid or alkali.
Define pI and explain its relationship to the net charge on a polyfunctional electrolyte.
Explain how pH, pKa and pI can be used to predict the mobility of a polyelectrolyte, such as an amino acid, in a directcurrent electrical field.
Describe the directionality, nomenclature, and primary structure of peptides.
Describe the conformational consequences of the partial doublebond character of the peptide bond and identify the bonds in the peptide
backbone that are free to rotate.
BIOMEDICAL IMPORTANCE
In addition to providing the monomer units from which the long polypeptide chains of proteins are synthesized, the lαamino acids and their
derivatives participate in cellular functions as diverse as nerve transmission and the biosynthesis of porphyrins, purines, pyrimidines, and urea. The
neuroendocrine system employs short polymers of amino acids called peptides as hormones, hormonereleasing factors, neuromodulators, and
neurotransmitters. Humans and other higher animals cannot synthesize 10 of the lαamino acids present in proteins in amounts adequate to support
infant growth or to maintain adult health. Consequently, the human diet must contain adequate quantities of these nutritionally essential amino acids.
Each day the kidneys filter over 50 g of free amino acids from the arterial renal blood. However, only traces of free amino acids normally appear in the
urine because amino acids are almost totally reabsorbed in the proximal tubule, conserving them for protein synthesis and other vital functions. Not
all amino acids are, however, beneficial. While their proteins contain only lαamino acids, some microorganisms secrete mixtures of damino acids.
Many bacteria elaborate peptides that contain both d and lαamino acids, several of which possess therapeutic value, including the antibiotics
bacitracin and gramicidin A and the antitumor agent bleomycin. Certain other microbial peptides are toxic. The cyanobacterial peptides microcystin
and nodularin are lethal in large doses, while small quantities promote the formation of hepatic tumors. The ingestion of certain amino acids present
in the seeds of legumes of the genus Lathyrus results in lathyrism, a tragic irreversible disease in which individuals lose control of their limbs. Certain
other plant seed amino acids have also been implicated in neurodegenerative disease in natives of Guam.
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PROPERTIES OF AMINO ACIDS
CHAPTER 3: Amino Acids &amp; Peptides, Peter J. Kennelly; Victor W. Rodwell Page 1 / 14
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The Genetic Code Specifies 20 l αAmino Acids
Many bacteria elaborate peptides that contain both d and lαamino acids, several of which possess therapeutic value, including the antibiotics
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bacitracin and gramicidin A and the antitumor agent bleomycin. Certain other microbial peptides are toxic. The cyanobacterial peptides microcystin
and nodularin are lethal in large doses, while small quantities promote the formation of hepatic tumors. The ingestion of certain amino acids present
in the seeds of legumes of the genus Lathyrus results in lathyrism, a tragic irreversible disease in which individuals lose control of their limbs. Certain
other plant seed amino acids have also been implicated in neurodegenerative disease in natives of Guam.
PROPERTIES OF AMINO ACIDS
The Genetic Code Specifies 20 l αAmino Acids
Although more than 300 amino acids occur in nature, proteins are synthesized almost exclusively from the set of 20 lαamino acids encoded by
nucleotide triplets called codons (see Table 37–1). While the threeletter genetic code could potentially accommodate more than 20 amino acids, the
genetic code is redundant since several amino acids are specified by multiple codons. Scientists frequently represent the sequences of peptides and
proteins using one and threeletter abbreviations for each amino acid (Table 3–1). These amino acids can be characterized as being either
hydrophilic or hydrophobic (Table 3–2), properties that affect their location in a protein’s mature folded conformation (see Chapter 5). Some
proteins contain additional amino acids that arise by the posttranslational modification of an amino acid already present in a peptide. Examples
include the conversion of peptidyl proline and peptidyl lysine to 4hydroxyproline and 5hydroxylysine; the conversion of peptidyl glutamate to γ
carboxyglutamate; and the methylation, formylation, acetylation, prenylation, and phosphorylation of certain aminoacyl residues. These modifications
significantly extend the biologic diversity of proteins by altering their solubility, stability, catalytic activity, and interaction with other proteins.
TABLE 3–1
l αAmino Acids Present in Proteins
Name Symbol Structural Formula p K1 p K2 p K3
With Aliphatic Side Chains αCOOH αNH + R Group

3
Glycine Gly [G] 2.4 9.8
Alanine Ala [A] 2.4 9.9
Valine Val [V] 2.2 9.7
Leucine Leu [L] 2.3 9.7
Isoleucine Ile [I] 2.3 9.8
With Side Chains Containing Hydroxylic (OH) Groups
Serine Ser [S] 2.2 9.2 about 13
Threonine Thr [T] 2.1 9.1 about 13
Tyrosine Tyr [Y] See below.

With Side Chains Containing Sulfur Atoms αCOOH αNH3+ R Group
Cysteine Cys [C] 1.9 10.8 8.3

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Threonine Thr [T] 2.1 9.1 about 13
Tyrosine Tyr [Y] See below.
With Side Chains Containing Sulfur Atoms αCOOH αNH3+ R Group
Cysteine Cys [C] 1.9 10.8 8.3
Methionine Met [M] 2.1 9.3
With Side Chains Containing Acidic Groups or Their Amides
Aspartic acid Asp [D] 2.1 9.9 3.9
Asparagine Asn [N] 2.1 8.8
Glutamic acid Glu [E] 2.1 9.5 4.1
Glutamine Gin [Q] 2.2 9.1
With Side Chains Containing Basic Groups
Arginine Arg [R] 1.8 9.0 12.5
Lysine Lys [K] 2.2 9.2 10.8
Histidine His [H] 1.8 9.3 6.0
Containing Aromatic Rings
Histidine His [H] See above.
Phenylalanine Phe [F] 2.2 9.2
Tyrosine Tyr [Y] 2.2 9.1 10.1
Tryptophan Trp [W] 2.4 9.4
CHAPTER 3: Amino Acids &amp; Peptides, Peter J. Kennelly; Victor W. Rodwell
Imino Acid
Page 3 / 14
Proline Pro [P] 2.0 10.6
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Tyrosine Tyr [Y] 2.2 9.1 10.1
Tryptophan Trp [W] 2.4 9.4
Imino Acid
Proline Pro [P] 2.0 10.6
TABLE 3–2
Hydrophilic & Hydrophobic Amino Acids
Hydrophilic Hydrophobic
Arginine Alanine
Asparagine Isoleucine
Aspartic acid Leucine
Cysteine Methionine
Glutamic acid Phenylalanine
Glutamine Proline
Glycine Tryptophan
Histidine Tyrosine
Lysine Valine
Serine
Threonine
The distinction is based on the tendency to associate with, or to minimize contact with, an aqueous environment.
Selenocysteine, the 21st Protein l αAmino Acid
Selenocysteine (Figure 3–1) is an lαamino acid found in proteins from every domain of life. Humans contain approximately two dozen
selenoproteins that include certain peroxidases and reductases, selenoprotein P, which circulates in the plasma, and the iodothyronine deiodinases
responsible for converting the prohormone thyroxine (T4) to the thyroid hormone 3,3'5triiodothyronine (T3) (see Chapter 41). As its name implies, a
selenium atom replaces the sulfur of its elemental analog, cysteine. Selenocysteine is not the product of a posttranslational modification, but is
inserted directly into a growing polypeptide during translation. Selenocysteine thus is commonly termed the “21st amino acid.” However, unlike the
other 20 protein amino acids, incorporation of selenocysteine is specified by a large and complex genetic element for the unusual tRNA called tRNASec
which utilizes the UGA anticodon that normally signals STOP. However, the protein synthetic apparatus can identify a selenocysteinespecific UGA
codon by the presence of an accompanying stemloop structure, the selenocysteine insertion element, in the untranslated region of the mRNA (see
Chapter 27).
FIGURE 3–1
Cysteine (left) & selenocysteine (right). pK3, for the selenyl proton of selenocysteine is 5.2. Since this is 3 pH units lower than that of cysteine,
selenocysteine represents a better nucleophile at or below pH 7.4.
FIGURE 3–1
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Cysteine (left) & selenocysteine (right). pK3, for the selenyl proton of selenocysteine is 5.2. Since this is 3 pH units lower than that of cysteine,
selenocysteine represents a better nucleophile at or below pH 7.4.
Stereochemistry of the Protein Amino Acids
With the sole exception of glycine, the αcarbon of every amino acid is chiral. Although some protein amino acids are dextrorotatory and some
levorotatory, all share the absolute configuration of lglyceraldehyde and thus are defined as lαamino acids. Even though almost all protein amino
acids are (R), the failure to use (R) or (S) to express absolute stereochemistry is no mere historical aberration. lCysteine is (S) since the atomic mass of
the sulfur atom on C3 exceeds that of the amino group on C2. More significantly, in mammals the biochemical reactions of lαamino acids, their
precursors and their catabolites are catalyzed by enzymes that act exclusively on lisomers, irrespective of their absolute configuration.
Posttranslational Modifications Confer Additional Properties
While some prokaryotes incorporate pyrrolysine into proteins, and plants can incorporate azetidine2carboxylic acid, an analog of proline, a set of
just 21 lαamino acids clearly suffices for the formation of most proteins. Posttranslational modifications can, however, generate novel Rgroups that
impart further properties. In collagen, for example, proteinbound proline and lysine residues are converted to 4hydroxyproline and 5hydroxylysine
(Figure 3–2). The carboxylation of glutamyl residues of proteins of the coagulation cascade to γcarboxyglutamyl residues (Figure 3–3) forms a
chelating group for the calcium ion essential for blood coagulation. The amino acid side chains of histones are subject to numerous modifications,
including acetylation and methylation of lysine and methylation and deamination of arginine (see Chapters 35 and 37). It also now is possible in the
laboratory to genetically introduce many different unnatural amino acids into proteins, generating proteins via recombinant gene expression with new
or enhanced properties and providing a new way to explore protein structurefunction relationships.
FIGURE 3–2
4Hydroxyproline & 5hydroxylysine.
FIGURE 3–3
fCarboxyglutamic acid.
Extraterrestrial Amino Acids Have Been Detected in Meteorites
In February 2013, the explosion of an approximately 20,000 metric ton meteor in the skies above Chelyabinsk, Western Siberia, dramatically
demonstrated the potential destructive power of those extraterrestrial bodies. However, not all the effects of meteors are necessarily undesirable.
Some meteorites, the remnants of asteroids that have reached earth, contain traces of several αamino acids. These include the protein amino acids
Ala, Asp, Glu, Gly, Ile, Leu, Phe, Ser, Thr, Tyr, and Val, as well as biologically important nonprotein αamino acids such as Nmethylglycine (sarcosine)
and βalanine.
Extraterrestrial amino acids were first reported in 1969 following analysis of the famous Murchison meteorite from southeastern Australia. The
presence of amino acids in other meteorites, including some pristine examples from Antarctica, has now been amply confirmed. Unlike terrestrial
amino acids, these meteorites contain racemic mixtures of d and lisomers of 3 to 5carbon amino acids, as well as many additional amino acids that
lack terrestrial counterparts of biotic origin. In addition, nucleobases, activated phosphates and molecules related to sugars have also been detected
in meteorites. These findings offer potential insights into the prebiotic chemistry of Earth, and impact the search for extraterrestrial life. Some
speculate that, by delivering extraterrestrially generated organic molecules to the early earth, meteorites may have contributed to the origin of life on
Some meteorites, the remnants of asteroids that have reached earth, contain traces of several αamino acids. These include the protein amino acids
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Ala, Asp, Glu, Gly, Ile, Leu, Phe, Ser, Thr, Tyr, and Val, as well as biologically important nonprotein αamino acids such as Nmethylglycine (sarcosine)
and βalanine.
Extraterrestrial amino acids were first reported in 1969 following analysis of the famous Murchison meteorite from southeastern Australia. The
presence of amino acids in other meteorites, including some pristine examples from Antarctica, has now been amply confirmed. Unlike terrestrial
amino acids, these meteorites contain racemic mixtures of d and lisomers of 3 to 5carbon amino acids, as well as many additional amino acids that
lack terrestrial counterparts of biotic origin. In addition, nucleobases, activated phosphates and molecules related to sugars have also been detected
in meteorites. These findings offer potential insights into the prebiotic chemistry of Earth, and impact the search for extraterrestrial life. Some
speculate that, by delivering extraterrestrially generated organic molecules to the early earth, meteorites may have contributed to the origin of life on
our planet.
l αAmino Acids Serve Additional Metabolic Roles
lαAmino acids fulfill vital metabolic roles in addition to serving as the “building blocks” of proteins. As discussed in later chapters, thyroid hormones
are formed from tyrosine; glutamate serves as a neurotransmitter as well as the precursor of γaminobutyric acid (GABA); ornithine and citrulline are
intermediates in urea biosynthesis; and homocysteine, homoserine, and glutamateγsemialdehyde participate in the intermediary metabolism of the
protein amino acids (Table 3–3). The protein amino acids phenylalanine and tyrosine serve as precursors of epinephrine, norepinephrine, and DOPA
(dihydroxyphenylalanine).
TABLE 3–3
Examples of Nonprotein l αAmino Acids
Amino Acid Function
Intermediate in urea synthesis (Figure 2813).
Intermediate in urea synthesis (Figure 2813).
Intermediate in cysteine biosynthesis (Figure 279).
Product of cysteine biosynthesis (Figure 279).
Serine catabolite (Figure 293).
Certain Plant l αAmino Acids Can Adversely Impact Human Health
The consumption of certain nonprotein amino acids present in plants can adversely impact human health. The seeds and seed products of three
species of the legume Lathyrus have been implicated in the genesis of neurolathyrism, a profound neurological disorder characterized by progressive
and irreversible spastic paralysis of the legs. Lathyrism occurs widely during famines, when Lathyrus seeds represent a major contribution to the diet.
lαAmino acids that have been implicated in human neurologic disorders, notably neurolathyrism (Table 3–4) include lhomoarginine and βNoxalyl
α,βdiaminopropionic acid (βODAP). The seeds of the “sweet pea,” a Lathyrus legume that is widely consumed during famines, contain the
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osteolathyrogen γglutamylβaminopropionitrile (BAPN), a glutamine derivative of βaminopropionitrile (structure not shown). The seeds of certain
Lathyrus species also contain α,γdiaminobutyric acid, an analog of ornithine, that inhibits the hepatic urea cycle enzyme ornithine
transcarbamoylase. The resulting disruption of the urea cycle leads to ammonia toxicity. Finally, lβmethylaminoalanine, a neurotoxic amino acid
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The consumption of certain nonprotein amino acids present in plants can adversely impact human health. The seeds and seed products of three
species of the legume Lathyrus have been implicated in the genesis of neurolathyrism, a profound neurological disorder characterized by progressive
and irreversible spastic paralysis of the legs. Lathyrism occurs widely during famines, when Lathyrus seeds represent a major contribution to the diet.
lαAmino acids that have been implicated in human neurologic disorders, notably neurolathyrism (Table 3–4) include lhomoarginine and βNoxalyl
lα,βdiaminopropionic acid (βODAP). The seeds of the “sweet pea,” a Lathyrus legume that is widely consumed during famines, contain the
osteolathyrogen γglutamylβaminopropionitrile (BAPN), a glutamine derivative of βaminopropionitrile (structure not shown). The seeds of certain
Lathyrus species also contain α,γdiaminobutyric acid, an analog of ornithine, that inhibits the hepatic urea cycle enzyme ornithine
transcarbamoylase. The resulting disruption of the urea cycle leads to ammonia toxicity. Finally, lβmethylaminoalanine, a neurotoxic amino acid
present in Cycad seeds, has been implicated as a risk factor for neurodegenerative diseases including amyotrophic lateral sclerosisParkinson
dementia complex in natives of Guam who consume either fruit bats that feed on cycad fruit, or flour made from cycad seeds.
TABLE 3–4
Potentially Toxic l αAmino Acids
Nonprotein l αAmino Acid Medical Relevance
Cleaved by arginase to llysine and urea. Implicated in human neurolathyrism.
A neurotoxin. Implicated in human neurolathyrism.
An osteolathyrogen.
Inhibits ornithine transcarbamylase, resulting in ammonia toxicity.
Possible risk factor for neurodegenerative diseases.
d Amino Acids
dAmino acids that occur naturally include free dserine and daspartate in brain tissue, dalanine and dglutamate in the cell walls of grampositive
bacteria, and damino acids in certain peptides and antibiotics produced by bacteria, fungi, reptiles, and other nonmammalian species. Bacillus subtilis
excretes dmethionine, dtyrosine, dleucine, and dtryptophan to trigger biofilm disassembly, and Vibrio cholerae incorporates dleucine and d
methionine into the peptide component of their peptidoglycan layer.
PROPERTIES OF THE FUNCTIONAL GROUPS OF AMINO ACIDS
Amino Acids May Have Positive, Negative, or Zero Net Charge
In aqueous solution, the charged and uncharged forms of the ionizable weak acid groups —COOH and —NH3+ exist in dynamic protonic equilibrium:
methionine into the peptide component of their peptidoglycan layer.
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PROPERTIES OF THE FUNCTIONAL GROUPS OF AMINO ACIDS
Amino Acids May Have Positive, Negative, or Zero Net Charge
In aqueous solution, the charged and uncharged forms of the ionizable weak acid groups —COOH and —NH3+ exist in dynamic protonic equilibrium:
While both R—COOH and R—NH3+ are weak acids, R—COOH is a far stronger acid than R—NH3+. Thus, at physiologic pH (pH 7.4), carboxyl groups exist
almost entirely as R—COO– and amino groups predominantly as R—NH3+. The imidazole group of histidine and the guanidino group of arginine exist as
resonance hybrids with positive charge distributed between two nitrogens (histidine) or three nitrogens (arginine) (Figure 3–4). Figures 3–5 and 3 –
6 illustrate the effect that the pH of the aqueous environment has on the charged state of aspartic acid and lysine, respectively.
FIGURE 3–4
Resonance hybrids of the protonated R groups of histidine (TOP) and arginine (BOTTOM).
FIGURE 3–5
Protonic equilibria of aspartic acid.
Molecules that contain an equal number of positively and negativelycharged groups bear no net charge. These ionized neutral species are termed
zwitterions. Amino acids in blood and most tissues thus should be represented as in A , below.
Structure B cannot exist in aqueous solution because at any pH low enough to protonate the carboxyl group, the amino group would also be
protonated. Similarly, at any pH sufficiently high for an uncharged amino group to predominate, a carboxyl group will be present as R—COO–. The
uncharged representation B is, however, often used when diagramming reactions that do not involve protonic equilibria.
p K a Values Express the Strengths of Weak Acids
The strengths of weak acids are expressed as their p K a . For molecules with multiple dissociable protons, the pKa for each acidic group is designated by
replacing the subscript “a” with a number. The net charge on an amino acid—the algebraic sum of all the positively and negatively charged groups
present—depends upon the pKa values of its functional groups and the pH of the surrounding medium. In the laboratory, altering the charge on amino
acids and their derivatives by varying the pH facilitates the physical separation of amino acids, peptides, and proteins (see Chapter 4).
FIGURE 3–6
p K a Values Express the Strengths of Weak Acids Access Provided by:
The strengths of weak acids are expressed as their p K a . For molecules with multiple dissociable protons, the pKa for each acidic group is designated by
replacing the subscript “a” with a number. The net charge on an amino acid—the algebraic sum of all the positively and negatively charged groups
present—depends upon the pKa values of its functional groups and the pH of the surrounding medium. In the laboratory, altering the charge on amino
acids and their derivatives by varying the pH facilitates the physical separation of amino acids, peptides, and proteins (see Chapter 4).
FIGURE 3–6
Protonic equilibria of lysine.
At Its Isoelectric pH (pI), an Amino Acid Bears No Net Charge
Zwitterions are one example of an isoelectric species—the form of a molecule that has an equal number of positive and negative charges and thus is
electrically neutral. The isoelectric pH, also called the pI, is the pH midway between pKa values for the ionizations on either side of the isoelectric
species. For an amino acid such as alanine that has only two dissociating groups, there is no ambiguity. The first pKa (R—COOH) is 2.35 and the second
pKa (R—NH3+) is 9.69. The isoelectric pH (pI) of alanine thus is
For polyprotic acids, pI is also the pH midway between the pKa values on either side of the isoionic species. For example, the pI for aspartic acid is
For lysine, pI is calculated from:
Similar considerations apply to all polyprotic acids (eg, proteins), regardless of the number of dissociable groups present. In the clinical laboratory,
knowledge of the pI guides selection of conditions for electrophoretic separations. For example, two simple amino acids (with one COOH and one NH3+
group) can be separated by electrophoresis either at an acidic or basic pH that exploits subtle differences in net charge based on subtle differences in
pK1 or pK2 values. Similar considerations apply to understanding chromatographic separations on ionic supports such as diethylaminoethyl (DEAE)
cellulose (see Chapter 4).
p K a Values Vary With the Environment
The environment of a dissociable group affects its pKa (Table 3–5). A nonpolar environment, which possesses less capacity than water for stabilizing
charged species, thus raises the pKa of a carboxyl group making it a weaker acid, but lowers the pKa of an amino group, making it a stronger acid.
Similarly, the presence of an adjacent oppositely charged group can stabilize, or of a similarly charged group can destabilize, a developing charge.
Therefore, the pKa values of the R groups of free amino acids in aqueous solution (see Table 3–1) provide only an approximate guide to their pKa
values when present in proteins. The pKa of an amino acid’s side chain thus will depend upon its location within a given protein. pKa values that
diverge from aqueous solution by as much a 3 pH units are common at the active sites of enzymes. An extreme example, a buried aspartic acid of
thioredoxin, has a pKa above 9—a shift of more than 6 pH units!
TABLE 3–5
Typical Range of pK a Values for Ionizable Groups in Proteins
Dissociating Group p K a Range
Therefore, the pKa values of the R groups of free amino acids in aqueous solution (see Table 3–1) provide only an approximate guide to their pKa
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values when present in proteins. The pKa of an amino acid’s side chain thus will depend upon its location within a given protein. pKa values that
diverge from aqueous solution by as much a 3 pH units are common at the active sites of enzymes. An extreme example, a buried aspartic acid of
thioredoxin, has a pKa above 9—a shift of more than 6 pH units!
TABLE 3–5
Typical Range of pK a Values for Ionizable Groups in Proteins
Dissociating Group p K a Range
αCarboxyl 3.5–4.0
Nonα COOH of Asp or Glu 4.0–4.8
Imidazole of His 6.5–7.4
SH of Cys 8.5–9.0
OH of Tyr 9.5–10.5
αAmino 8.0–9.0
εAmino of Lys 9.8–10.4
Guanidinium of Arg ~12.0
The Solubility of Amino Acids Reflects Their Ionic Character
The charges conferred by the dissociable functional groups of amino acids ensure that they are readily solvated by—and thus soluble in—polar
solvents such as water and ethanol but insoluble in nonpolar solvents such as benzene, hexane, or ether.
Amino acids do not absorb visible light and thus are colorless. However, tyrosine, phenylalanine, and especially tryptophan absorb highwavelength
(250290 nm) ultraviolet light. Because it absorbs ultraviolet light about ten times more efficiently than either phenylalanine or tyrosine, tryptophan
makes the major contribution to the ability of most proteins to absorb light in the region of 280 nm (Figure 3–7).
FIGURE 3–7
Ultraviolet absorption spectra of tryptophan, tyrosine, and phenylalanine.
THE αR GROUPS DETERMINE THE PROPERTIES OF AMINO ACIDS
Each functional group of an amino acid exhibits all of its characteristic chemical reactions. For carboxylic acid groups, these reactions include the
formation of esters, amides, and acid anhydrides; for amino groups, acylation, amidation, and esterification; and for —OH and —SH groups, oxidation
and esterification. Since glycine, the smallest amino acid, can be accommodated in places inaccessible to other amino acids, it often occurs where
peptides bend sharply. The hydrophobic R groups of alanine, valine, leucine, and isoleucine and the aromatic R groups of phenylalanine, tyrosine, and
tryptophan typically occur primarily in the interior of cytosolic proteins. The charged R groups of basic and acidic amino acids stabilize specific protein
conformations via ionic interactions, or salt bridges. These interactions also function in “charge relay’’ systems during enzymatic catalysis and electron
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THE αR GROUPS DETERMINE THE PROPERTIES OF AMINO ACIDS
Each functional group of an amino acid exhibits all of its characteristic chemical reactions. For carboxylic acid groups, these reactions include the
formation of esters, amides, and acid anhydrides; for amino groups, acylation, amidation, and esterification; and for —OH and —SH groups, oxidation
and esterification. Since glycine, the smallest amino acid, can be accommodated in places inaccessible to other amino acids, it often occurs where
peptides bend sharply. The hydrophobic R groups of alanine, valine, leucine, and isoleucine and the aromatic R groups of phenylalanine, tyrosine, and
tryptophan typically occur primarily in the interior of cytosolic proteins. The charged R groups of basic and acidic amino acids stabilize specific protein
conformations via ionic interactions, or salt bridges. These interactions also function in “charge relay’’ systems during enzymatic catalysis and electron
transport in respiring mitochondria. Histidine plays unique roles in enzymatic catalysis. The pKa of its imidazole proton permits histidine to function at
neutral pH as either a base or an acid catalyst without the need for any environmentally induced shift. The primary alcohol group of serine and the
primary thioalcohol (—SH) group of cysteine are excellent nucleophiles, and can function as such during enzymatic catalysis. The pK3 of
selenocysteine, 5.2, is 3 units lower than that of cysteine, so that it should, in principle, be the better nucleophile. However, the secondary alcohol
group of threonine, while a good nucleophile, is not known to fulfill an analogous role in catalysis. The —OH groups of serine, tyrosine, and threonine
frequently serve as the points of covalent attachment for phosphoryl groups that regulate protein function (see Chapter 9).
Amino Acid Sequence Determines Primary Structure
Amino acids are linked together by peptide bonds.
The number and order of the amino acid residues in a polypeptide constitute its primary structure. Amino acids present in peptides are called
aminoacyl residues, and are referred to by replacing the ate or ine suffixes of free amino acids with yl (eg, alanyl, aspartyl, tyrosyl). Peptides are then
named as derivatives of the carboxy terminal aminoacyl residue. For example, LysLeuTyrGln is called lysylleucyltyrosylglutamine. The ine ending
on the carboxyterminal residue (eg, glutamine) indicates that its αcarboxyl group is not involved in a peptide bond. Threeletter abbreviations linked
by straight lines represent an unambiguous primary structure. Lines are omitted when using singleletter abbreviations.
Prefixes like tri or octa denote peptides with three or eight residues, respectively. By convention, peptides are written with the residue that bears the
free αamino group at the left. This convention was adopted long before it was discovered that peptides are synthesized in vivo starting from the
aminoterminal residue.
Peptide Structures Are Easy to Draw
To draw a peptide, use a zigzag to represent the main chain or backbone. Add the main chain atoms, which occur in the repeating order: αnitrogen, α
carbon, carbonyl carbon. Now add a hydrogen atom to each αcarbon and to each peptide nitrogen, and an oxygen to the carbonyl carbon. Finally, add
the appropriate R groups (shaded) to each αcarbon atom.
Some Peptides Contain Unusual Amino Acids
In mammals, peptide hormones typically contain only the 20 codonspecified αamino acids linked by standard peptide bonds. Other peptides may,
however, contain nonprotein amino acids, derivatives of the protein amino acids, or amino acids linked by an atypical peptide bond. For example, the
amino terminal glutamate of glutathione, a tripeptide that participates in the metabolism of xenobiotics (see Chapter 47) and the reduction of disulfide
bonds, is linked to cysteine by a nonα peptide bond (Figure 3–8). The amino terminal glutamate of thyrotropinreleasing hormone (TRH) is cyclized
to pyroglutamic acid, and the carboxyl group of the carboxyl terminal prolyl residue is amidated. The nonprotein amino acids dphenylalanine and
ornithine are present in the cyclic peptide antibiotics tyrocidin and gramicidin S, while the heptapeptide opioids dermorphin and deltophorin in the
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Some Peptides Contain Unusual Amino Acids
In mammals, peptide hormones typically contain only the 20 codonspecified αamino acids linked by standard peptide bonds. Other peptides may,
however, contain nonprotein amino acids, derivatives of the protein amino acids, or amino acids linked by an atypical peptide bond. For example, the
amino terminal glutamate of glutathione, a tripeptide that participates in the metabolism of xenobiotics (see Chapter 47) and the reduction of disulfide
bonds, is linked to cysteine by a nonα peptide bond (Figure 3–8). The amino terminal glutamate of thyrotropinreleasing hormone (TRH) is cyclized
to pyroglutamic acid, and the carboxyl group of the carboxyl terminal prolyl residue is amidated. The nonprotein amino acids dphenylalanine and
ornithine are present in the cyclic peptide antibiotics tyrocidin and gramicidin S, while the heptapeptide opioids dermorphin and deltophorin in the
skin of South American tree frogs contain dtyrosine and dalanine.
FIGURE 3–8
Glutathione (γglutamylcysteinylglycine). Note the nonα peptide bond that links Glu to Cys.
The Peptide Bond Has Partial DoubleBond Character
Although peptide structures are written as if a single bond linked the αcarboxyl and αnitrogen atoms, this bond in fact exhibits partial doublebond
character:
Hence, the bond that connects a carbonyl carbon to an αnitrogen cannot rotate, as this would require breaking the partial double bond. Therefore,
the O, C, N, and H atoms of a peptide bond are coplanar. The imposed semirigidity of the peptide bond has important consequences for the manner in
which peptides and proteins fold to generate higher orders of structure. Encircling brown arrows indicate free rotation about the remaining bonds of
the polypeptide backbone (Figure 3–9).
FIGURE 3–9
Dimensions of a fully extended polypeptide chain. The four atoms of the peptide bond are coplanar. Free rotation can occur about the bonds
that connect the αcarbon with the αnitrogen and with the αcarbonyl carbon (brown arrows). The extended polypeptide chain is thus a semirigid
structure with twothirds of the atoms of the backbone held in a fixed planar relationship one to another. The distance between adjacent αcarbon
atoms is 0.36 nm (3.6 Å). The interatomic distances and bond angles, which are not equivalent, are also shown. (Redrawn and reproduced, with
permission, from Pauling L, Corey LP, Branson HR: The structure of proteins: Two hydrogenbonded helical configurations of the polypeptide chain.
Proc Natl Acad Sci USA 1951;37:205.)
Noncovalent Forces Constrain Peptide Conformations
Folding of a peptide probably occurs coincident with its biosynthesis (see Chapter 37). The mature, physiologically active conformation reflects the
collective contributions of the amino acid sequence, noncovalent interactions (eg, hydrogen bonding, hydrophobic interactions), and the
minimization of steric hindrance between residues. Common repeating conformations include αhelices and βpleated sheets (see Chapter 5).
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Noncovalent Forces Constrain Peptide Conformations
Folding of a peptide probably occurs coincident with its biosynthesis (see Chapter 37). The mature, physiologically active conformation reflects the
collective contributions of the amino acid sequence, noncovalent interactions (eg, hydrogen bonding, hydrophobic interactions), and the
minimization of steric hindrance between residues. Common repeating conformations include αhelices and βpleated sheets (see Chapter 5).
Peptides Are Polyelectrolytes
The peptide bond is uncharged at any pH of physiologic interest. Formation of peptides from amino acids is therefore accompanied by a net loss of
one positive and one negative charge per peptide bond formed. Peptides nevertheless are charged at physiologic pH owing to their terminal carboxyl
and amino groups and, where present, their acidic or basic R groups. As for amino acids, the net charge on a peptide depends on the pH of its
environment and on the pKa values of its dissociating groups.
ANALYSIS OF THE AMINO ACID CONTENT OF BIOLOGIC MATERIALS
As discussed in Chapter 4, the amino acid content of proteins generally is extrapolated from the DNA sequence of the encoding gene, or directly
analyzed by mass spectrometry. The following material, while primarily of historical interest, can still find applications, for example, in the detection of
abnormal quantities of urinary amino acids when modern equipment is lacking. Free amino acids released by cleavage of peptide bonds in hot
hydrochloric acid can be separated and identified by highpressure liquid chromatography (HPLC) or by paper chromatography (TLC) that employ a
mobile phase composed of a mixture of miscible polar and nonpolar components (eg, nbutanol, formic acid, and water). As the mobile phase moves
up the sheet or down a column it becomes progressively enriched in the less polar constituents. Nonpolar amino acids (eg, Leu, Ile) therefore travel the
farthest while polar amino acids (eg, Glu, Lys) travel the least distance from the origin. Amino acids can then be visualized using ninhydrin, which forms
purple products with most αamino acids but a yellow adduct with proline and hydroxyproline.
SUMMARY
Both damino acids and nonαamino acids occur in nature, but proteins are synthesized using only lαamino acids. dAmino acids do, however,
serve metabolic roles, not only in bacteria, but also in humans.
lαAmino acids serve vital metabolic functions in addition to protein synthesis. Examples include the biosynthesis of urea, heme, nucleic acids,
and hormones such as epinephrine and DOPA.
The presence in meteorites of trace quantities of many of the protein amino acids lends credence to the hypothesis that asteroid strikes might
have contributed to the development of life on earth.
Certain of the lαamino acids present in plants and plant seeds can have deleterious effects on human health, for example in lathyrism.
The R groups of amino acids determine their unique biochemical functions. Amino acids are classified as basic, acidic, aromatic, aliphatic, or
sulfurcontaining based on the composition and properties of their R groups.
The partial doublebond character of the bond that links the carbonyl carbon and the nitrogen of a peptide render the four atoms of the peptide
bond coplanar, and hence restrict the number of possible peptide conformations.
Peptides are named for the number of amino acid residues present, and as derivatives of the carboxyl terminal residue. The primary structure of a
peptide is its amino acid sequence, starting from the aminoterminal residue, a direction in which peptides actually are synthesized in vivo.
All amino acids possess at least two weakly acidic functional groups, R—NH3+ and R—COOH. Many also possess additional weakly acidic functional
groups such as phenolic —OH, —SH, guanidino, or imidazole moieties.
The pKa values of all functional groups of an amino acid or of a peptide dictate its net charge at a given pH. pI, the isoelectric pH, is the pH at which
an amino acid bears no net charge, and thus does not move in a direct current electrical field.
The pKa values of free amino acids at best only approximate pKa values in a protein, which can differ widely due to the influence of the
CHAPTER 3: Amino Acids &amp; Peptides, Peter J. Kennelly; Victor W. Rodwell
surroundings in a protein.
Page 13 / 14
REFERENCES
groups such as phenolic —OH, —SH, guanidino, or imidazole moieties. Access Provided by:
The pKa values of all functional groups of an amino acid or of a peptide dictate its net charge at a given pH. pI, the isoelectric pH, is the pH at which
an amino acid bears no net charge, and thus does not move in a direct current electrical field.
The pKa values of free amino acids at best only approximate pKa values in a protein, which can differ widely due to the influence of the
surroundings in a protein.
REFERENCES
Bell EA: Nonprotein amino acids of plants. Significance in medicine, nutrition, and agriculture. J Agric Food Chem 2003;51:2854.
Bender, DA: Amino Acid Metabolism , 3rd ed. Wiley, 2012.
Burton AS, Stern JC, Elsila JE, et al.: Understanding prebiotic chemistry through the analysis of extraterrestrial amino acids and nucleobases in
meteorites. Chem Soc Rev 2012;41:5459.
KolodkinGal I: dAmino acids trigger biofilm disassembly. Science 2010;328:627.
Kreil G: dAmino acids in animal peptides. Annu Rev Biochem 1997;66:337.
deMunck E, MuñozSáez E, Miguel BG et al.: βNMethylaminoLalanine causes neurological and pathological phenotypes mimicking Amyotrophic
Lateral Sclerosis (ALS): The first step towards an experimental model for sporadic ALS. Environ Toxicol Pharmacol 2013;36:243.
Nokihara K, Gerhardt J: Development of an improved automated gaschromatographic chiral analysis system: application to nonnatural amino acids
and natural protein hydrolysates. Chirality 2001;13:431.
Papp LV: From selenium to selenoproteins: Synthesis, identity, and their role in human health. Antioxidants Redox Signal. 2007;9:775.
Wilson NA et al.: Aspartic acid 26 in reduced Escherichia coli thioredoxin has a pK a greater than 9. Biochemistry 1995;34:8931.

CHAPTER 3 - Amino Acids &amp Amp Peptides

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Name Symbol Structural Formula p K1 p K2 p K3

With Aliphatic Side Chains α­COOH α­NH + R Group

Glycine Gly [G] 2.4 9.8

Alanine Ala [A] 2.4 9.9

Valine Val [V] 2.2 9.7

Leucine Leu [L] 2.3 9.7

Isoleucine Ile [I] 2.3 9.8

Serine Ser [S] 2.2 9.2 about 13

Threonine Thr [T] 2.1 9.1 about 13

Tyrosine Tyr [Y] See below.

Cysteine Cys [C] 1.9 10.8 8.3

Threonine Thr [T] 2.1 9.1 about 13

Tyrosine Tyr [Y] See below.

With Side Chains Containing Sulfur Atoms α­COOH α­NH3+ R Group

Cysteine Cys [C] 1.9 10.8 8.3

Methionine Met [M] 2.1 9.3

Aspartic acid Asp [D] 2.1 9.9 3.9

Asparagine Asn [N] 2.1 8.8

Glutamic acid Glu [E] 2.1 9.5 4.1

Glutamine Gin [Q] 2.2 9.1

Arginine Arg [R] 1.8 9.0 12.5

Lysine Lys [K] 2.2 9.2 10.8

Histidine His [H] 1.8 9.3 6.0

Histidine His [H] See above.

Phenylalanine Phe [F] 2.2 9.2

Tyrosine Tyr [Y] 2.2 9.1 10.1

Tryptophan Trp [W] 2.4 9.4

Tyrosine Tyr [Y] 2.2 9.1 10.1

Tryptophan Trp [W] 2.4 9.4

Proline Pro [P] 2.0 10.6

Nonprotein l ­α­Amino Acid Medical Relevance

Wilson NA et al.: Aspartic acid 26 in reduced Escherichia coli thioredoxin has a pK a greater than 9. Biochemistry 1995;34:8931.

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With Aliphatic Side Chains αCOOH αNH + R Group

With Side Chains Containing Sulfur Atoms αCOOH αNH3+ R Group

Nonprotein l αAmino Acid Medical Relevance