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CHAPTER
3
Amino Acids
3.1 Proteins Are Built from a
Repertoire of 20 Amino Acids
3.2 Amino Acids Contain a Wide Array
of Functional Groups
3.3 Essential Amino Acids Must Be
Obtained from the Diet
In Lewis Carroll’s wonderful tale Through the Looking Glass, Alice enters a world of
delightful curiosities. Had Alice been a biochemist, she might have wondered if the
stereochemistry of the amino acids in Looking Glass proteins were mirror images of the
amino acids in her normal world. [The Granger Collection.]
T
he role of amino acids in life as the building blocks of proteins is readily apparent in health food stores. Indeed, their shelves are stocked with powdered
amino acids for use as dietary supplements so that body builders can enhance
muscle growth. However, amino acids are key biochemicals in their own right.
Some amino acids function as signal molecules such as neurotransmitters, and all
amino acids are precursors to other biomolecules, such as hormones, nucleic
acids, lipids and, as just mentioned, proteins. In this chapter, we examine the fundamental chemical properties of amino acids.
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33
3.1 Proteins Are Built from a Repertoire of
20 Amino Acids
3.1 Amino Acid Structure
Amino acids are the building blocks of proteins. An a-amino acid consists of a
central carbon atom, called the a carbon, linked to an amino group, a carboxylic
acid group, a hydrogen atom, and a side chain, called the R group. Each kind of
amino acid has a different R group.
Most Amino Acids Exist in Two Mirror-Image Forms
With four different groups connected to the tetrahedral ␣-carbon atom, ␣-amino
acids are chiral: they may exist in one or the other of two mirror-image forms,
called the L isomer and the D isomer (Figure 3.1).
H
R
R
H
Cα
Cα
NH3+
COO−
L
isomer
Figure 3.1 The L and D isomers of amino
acids. The letter R refers to the side chain.
The L and D isomers are mirror images of
each other.
+
COO−
NH3
D
isomer
Only L amino acids are constituents of proteins. Although considerable effort
has gone into understanding why amino acids in proteins have the L absolute
configuration, no satisfactory explanation has been reached. It seems plausible
that the selection of L over D was arbitrary but, once made, the selection was fixed
early in evolutionary history.
All Amino Acids Have at Least Two Charged Groups
Free amino acids in solution at neutral pH exist predominantly as dipolar ions
(also called zwitterions). In the dipolar form, the amino group is protonated
(NH3⫹) and the carboxyl group is deprotonated (COO⫺). The ionization state
of an amino acid varies with pH (Figure 3.2). In acid solution (e.g., pH 1), the
R
H
H+
C
+H
3N
COOH
+
H
R
H
C
+H
3N
H+
COO–
C
+
H
Zwitterionic form
Concentration
R
H
H2N
COO–
Both groups
deprotonated
Both groups
protonated
0
2
4
6
8
pH
10
12
14
Figure 3.2 Ionization state as a function
of pH. The ionization state of amino acids
is altered by a change in pH. The
zwitterionic form predominates near
physiological pH.
34
3 Amino Acids
amino group is protonated (NH3⫹) and the carboxyl group is not dissociated
( ¬COOH). As the pH is raised, the carboxylic acid is the first group to give up
a proton, because its pKa is near 2. The dipolar form persists until the pH
approaches 9, when the protonated amino group loses a proton. Under physiological conditions, amino acids exist in the dipolar form.
3.2 Amino Acids Contain a Wide Array of Functional Groups
Twenty kinds of side chains varying in size, shape, charge, hydrogen-bonding capacity,
hydrophobic character, and chemical reactivity are commonly found in proteins. Many
of these properties are conferred by functional groups. The amino acid functional
groups include alcohols, thiols, thioethers, carboxylic acids, carboxamides, and a variety of basic groups. Most of these groups are chemically reactive.
All proteins in all species—bacterial, archaeal, and eukaryotic—are
constructed from the same set of 20 amino acids with only a few exceptions. This
fundamental alphabet for the construction of proteins is several billion years old.
The remarkable range of functions mediated by proteins results from the diversity and versatility of these 20 building blocks.
Although there are many ways to classify amino acids, we will assort these
molecules into four groups, on the basis of the general chemical characteristics of
their R groups:
1. Hydrophobic amino acids with nonpolar R groups
2. Polar amino acids with neutral R groups but the charge is not evenly
distributed
3. Positively charged amino acids with R groups that have a positive charge at
physiological pH
4. Negatively charged amino acids with R groups that have a negative charge at
physiological pH
Hydrophobic Amino Acids Have Mainly Hydrocarbon Side Chains
The amino acids having side chains consisting only of hydrogen and carbon are
hydrophobic. The simplest amino acid is glycine, which has a single hydrogen
atom as its side chain. With two hydrogen atoms bonded to the ␣-carbon atom,
glycine is unique in being achiral. Alanine, the next simplest amino acid, has a
methyl group ( ¬CH3) as its side chain (Figure 3.3). The three-letter abbreviations and one-letter symbols under the names of the amino acids depicted in Figure 3.3 and in subsequent illustrations are an integral part of the vocabulary of
biochemists.
Larger hydrocarbon side chains are found in the branched-chain (aliphatic)
amino acids valine, leucine, and isoleucine. Methionine contains a largely aliphatic
side chain that includes a thioether ( ¬S¬ ) group. The different sizes and shapes
of these hydrocarbon side chains enable them to pack together to form compact
structures with little empty space. Proline also has an aliphatic side chain, but it
differs from other members of the set of 20 in that its side chain is bonded to both
the ␣-carbon and the nitrogen atom. Proline markedly influences protein architecture because its ring structure makes it more conformationally restricted than
the other amino acids.
Two amino acids with relatively simple aromatic side chains are also classified
as hydrophobic (see Figure 3.3). Phenylalanine, as its name indicates, contains a
phenyl ring attached in place of one of the methyl hydrogens of alanine.
Tryptophan has an indole ring joined to a methylene ( ¬CH2 ¬ ) group; the
indole group comprises two fused rings and an NH group.
The hydrophobic amino acids, particularly the larger aliphatic and aromatic
ones, tend to cluster together inside the protein away from the aqueous environment of the cell. This tendency of hydrophobic groups to come together is called
the hydrophobic effect (pp. 20–21) and is the driving force for the formation of the
H
H
C
+H
C
+H
COO–
3N
H
+H N
3
3.2 The 20 Amino Acids
CH3
H
COO–
3N
35
CH3
COO–
C
+
COO–
C
H3N
H
H
Glycine
(Gly, G)
Alanine
(Ala, A)
H3C
CH3
H3C
CH
H
C
+H
3N
HC
CH3
COO–
+
CH3
H2C
CH2
H
C
H3N
COO–
S
CH3
CH3
C H
H
+H
C
3N
H2
C
H2C
CH2
H
COO–
+H N
3
C
C
N+
H2
COO–
CH2
H
H2C
COO–
CH3
CH3
CH3
H
+H
3N
H
C
CH3
C
COO–
C
CH3
H
CH2
+H
3N
C
COO–
+H
3N
CH3
S
CH2
CH2
C
CH3
C
COO–
H2
C
CH2
+H
3N
C
H2C
CH2
N+
H2
COO–
COO–
C
H
H
H
H
H
Valine
(Val, V)
Leucine
(Leu, L)
Isoleucine
(Ile, I)
Methionine
(Met, M)
Proline
(Pro, P)
H
H
H
H
H
H
H
HN
H
H
H
CH2
H
C
+H N
3
C
COO–
CH
HC
HC
CH
HC
C
COO–
+H N
3
H
C
H
C
CH2
H
C
CH
C
HN
C
H
+H N
3
C
H
Figure 3.3 Hydrophobic amino acids.
C
H
CH2
Phenylalanine
(Phe, F)
COO–
C
CH2
+H N
3
C
H
Tryptophan
(Trp, W)
COO–
36
3 Amino Acids
unique three-dimensional architecture of water-soluble proteins. The different
sizes and shapes of these hydrocarbon side chains enable them to pack together
to form compact structures with little empty space.
Polar Amino Acids Have Side Chains That Contain
an Electronegative Atom
The next group of amino acids that we will consider are those that are neutral
overall, yet they are polar because the R group contains an electronegative atom
that hoards electrons. Three amino acids, serine, threonine and tyrosine contain
hydroxyl ( ¬OH) groups (Figure 3.4). The electrons in the O¬H bond are
attracted to the oxygen atom, making it partially negative, which in turn makes
the hydrogen partially positive. Serine can be thought of as a version of alanine
with a hydroxyl group attached to the methyl group, whereas threonine resembles
valine with a hydroxyl group in place of one of the valine methyl groups. Tyrosine
is similar to phenylalanine, but contains a hydrophilic hydroxyl group attached to
the large aromatic ring. The hydroxyl groups on serine, threonine, and tyrosine
make them more hydrophilic (water loving) and reactive than their respective nonpolar counterparts alanine, valine, and phenylalanine. Cysteine is structurally similar to serine but contains a sulfhydryl, or thiol ( ¬SH), group in place of the
H
H
O
H
O
H
CH2
H
C
+H N
COO–
3
H
CH3
H O
C
H
H
C
+H N
COO–
3
H
C
H
C
C
CH
OH
HC
CH2
+H N
3
H
COO–
C
COO–
+H N
3
HO
OH
CH2
H
+H N
3
H
C
CH3
C
COO–
C
C
H
+H N
3
CH2
C
H
Serine
(Ser, S)
COO–
H
Tyrosine
(Tyr, Y)
Threonine
(Thr, T)
H2N
H
O
CH2
H
C
NH2
S
C
+H N
3
COO–
C
CH2
H
+
C
H3N
COO–
CH2
H
C
+H
3N
O
C
O
SH
C
CH2
+H N
3
C
H
Figure 3.4 Polar amino acids.
Cysteine
(Cys, C)
NH2
+H
3N
C
COO–
NH2
CH2
CH2
COO–
O
H2C
CH2
COO–
+H
3N
C
COO–
H
H
Asparagine
(Asn, N)
Glutamine
(Gln, Q)
H2N
NH3+
NH2
3.2 The 20 Amino Acids
HN
H2C
CH2
CH2
C
+H N
3
CH2
H
CH2
H
C
COO–
H2N
+
C H
H
NH2
C
COO–
+H N
3
NH
CH2
CH2
CH2
CH2
CH2
CH2
+H N
3
C
N
C
CH2
COO–
H
COO–
+H N
3
NH3+
C
H
N
H2C
H2C
+H N
3
37
+
C
H
N
C
N
COO–
C
CH
HC
CH2
+H N
3
C
COO–
H
H
H
Lysine
(Lys, K)
Arginine
(Arg, R)
Histidine
(His, H)
hydroxyl group. The sulfhydryl group is much more reactive than a hydroxyl
group and can completely lose a proton at slightly basic pH to form the reactive
thiolate group. Pairs of sulfhydryl groups in close proximity may form disulfide
bonds, covalent bonds that are particularly important in stabilizing some proteins, as will be discussed in Chapter 4. In addition, the set of polar amino acids
includes asparagine and glutamine, which contain a terminal carboxamide.
Positively Charged Amino Acids Are Hydrophilic
We now turn to amino acids having positively charged side chains that render
these amino acids highly hydrophilic (Figure 3.5). Lysine and arginine have relatively long side chains that terminate with groups that are positively charged at
neutral pH. Lysine is topped by an amino group and arginine by a guanidinium
group. Note that the R groups of lysine and arginine have dual properties—the
four-carbon chains constitute a hydrocarbon backbone, similar to the amino
acid leucine, but the chain is terminated with a positive charge. Such combinations of characteristics contribute to the wide array of chemical properties of
amino acids.
Histidine contains an imidazole group, an aromatic ring that also can be positively charged. With a pKa value near 6, the imidazole group of histidine is unique
in that it can be uncharged or positively charged near neutral pH, depending on
its local environment (Figure 3.6). Indeed, histidine is often found in the active
sites of enzymes, where the imidazole ring can bind and release protons in the
course of enzymatic reactions.
HC +
H
N
H
N
H+
C
CH2
H
C
N
H
C
O
Lysine is an essential amino acid (p. 39),
which means that human beings cannot
synthesize lysine and must obtain it in the
diet. In experimental animals, kept on a
cereal-based diet, inadequate dietary
lysine increased stress-induced anxiety.
Recent studies suggest that this response
to lysine deprivation may be true for
human beings, too.
NH2
+
C
NH2
H2N
Guanidinium
N
H C
H
C
N
C
H
H
Imidazole
H
N
HC
CH
Figure 3.5 Positively charged amino acids.
CH
N
C
H
H+
CH2
C
N
H
C
O
Figure 3.6 Histidine ionization. Histidine
can bind or release protons near
physiological pH.
38
Negatively Charged Amino Acids Have Acidic Side Chains
3 Amino Acids
The two amino acids in this group, aspartic acid and glutamic acid, have acidic
side chains that are usually negatively charged under intracellular conditions
(Figure 3.7). These amino acids are often called aspartate and glutamate to
emphasize the presence of the negative charge on their side chains. In some proteins, these side chains accept protons, which neutralize the negative charge. This
ability is often functionally important. Aspartate and glutamate are related to
asparagine and glutamine in which a carboxylic acid group in the former pair
replaces a carboxamide in the latter pair.
Monosodium glutamate (MSG), which is
glutamate with sodium bound to an acid
group, is commonly used as a taste
enhancer. In fact, the taste of glutamate
and aspartate (called umami, from the
Japanese word for “deliciousness”) is,
along with sweet, sour, bitter, and salty,
one of the five primary tastes.
The Ionizable Side Chains Enhance Reactivity and Bonding
QUICK QUIZ Name three amino
acids that are positively charged at
neutral pH. Name three amino acids that
contain hydroxyl groups.
O
+H
3N
C
COO–
–
C
+H
3N
O
3N
C
C
–
C
COO–
O
Group
+H
3N
C
Δ
Acid
Base
O
Terminal ␣-carboxyl group
CH2
COO–
Table 3.1 Typical pKa values of ionizable groups in proteins
CH2
CH2
+H
CH2
H
O
O
O
H2C
CH2
H
–
C
– O
O C
Seven of the 20 amino acids—tyrosine, cysteine, arginine, lysine, histidine, and
aspartic and glutamic acids—have readily ionizable side chains. These seven
amino acids are able to form ionic bonds as well as to donate or accept protons
to facilitate reactions. The ability to donate or accept protons is called
acid–base catalysis and is an important chemical reaction for many enzymes.
We will see the importance of histidine as an acid–base catalyst when we examine the protein-digesting enzyme chymotrypsin in Chapter 8. Table 3.1 gives
equilibria and typical pKa values for the ionization of the side chains of these
seven amino acids.
O
C
O
COO–
H
H
Aspartate
(Asp, D)
Glutamate
(Glu, E)
O
–
C
H
4.1
O
H
N
N
+
Histidine
N
N
H
6.0
H
+ H
Terminal ␣-amino group
N
N
H
H
H
Cysteine
8.0
H
H
8.3
S–
S
Tyrosine
O
H
O–
+ H
Lysine
N
N
H
H
H
+ N H
H
Arginine
3.1
O
O
C
Figure 3.7 Negatively charged amino
acids.
–
C
H
O
Aspartic acid
Glutamic acid
Typical pKa
N
C
H
N H
H
H
10.9
10.8
H
N
H
N
C
H
12.5
N H
Note: Values of pKa depend on temperature, ionic strength, and the microenvironment of the ionizable group.
Table 3.2 Basic set of 20 amino acids
39
Nonessential
Essential
Alanine
Arginine
Asparagine
Aspartate
Cysteine
Glutamate
Glutamine
Glycine
Proline
Serine
Tyrosine
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Valine
3.3 Essential Amino Acids
3.3 Essential Amino Acids Must Be Obtained
from the Diet
Most microorganisms can synthesize the entire basic set of 20 amino acids,
whereas human beings cannot make nine of them. Amino acids that cannot be
generated in the body must be supplied by the diet and are termed essential amino
acids. The others are called nonessential amino acids (Table 3.2). These designations refer to an organism under a particular set of conditions. For example, a
human adult can synthesize enough arginine to meet his or her needs, but a growing child requires more arginine than the body can provide.
Clinical Insight
Pathological Conditions Result If Protein
Intake Is Inadequate
The importance of amino acids in the diet (usually ingested as proteins) is illustrated by kwashiorkor, a particular form of malnutrition. Kwashiorkor means “the
disease of the displaced child” in the language of Ga, a Ghanaian dialect; that is,
the condition arises when a child is weaned because of the birth of a sibling. This
condition was first defined in the 1930s in Ghana. It is a form of malnutrition
that results when protein intake is not sufficient. Initial symptoms of the disease
are generalized lethargy, irritability, and stunted growth. If treated early enough,
the effects of the disease are reversible. However, if not corrected early enough,
many physiological systems fail to develop properly, including the brain. For
instance, children will suffer from various infectious diseases because their
immune systems, composed of many different proteins, cannot be constructed
to function adequately. Likewise, the lack of protein prevents the complete development of the central nervous system, with resulting neurological problems.
The most common characteristic of a child suffering from kwashiorkor is a
large protruding belly (Figure 3.8). The large belly is a sign not of excess calories
but of edema, another result of the lack of protein. Edema is swelling that results
from too much water in tissue. Insufficient protein in a child’s blood distorts the
normal distribution of water between plasma and surrounding capillaries.
Although the swollen belly is most obvious, the limbs of a child suffering from
kwashiorkor also are often swollen. Such suffering children are a devastating display of the centrality of protein to life. ■
Figure 3.8 A child suffering from
kwashiorkor. Note the swollen belly and
limbs. This swelling (edema) is due to fluid
collecting in the tissues because there is
not enough protein in the blood. [Stephen
Morrison/epa/Corbis.]
40
3 Amino Acids
SUMMARY
3.1
Proteins Are Built from a Repertoire of 20 Amino Acids
Proteins are linear polymers of amino acids. Each amino acid consists of a
central tetrahedral carbon atom linked to an amino group, a carboxylic acid
group, a distinctive side chain, and a hydrogen atom. These tetrahedral centers, with the exception of that of glycine, are chiral; only the L isomer exists
in natural proteins. All natural proteins are constructed from the same set
of 20 amino acids.
3.2
Amino Acids Contain a Wide Array of Functional Groups
The side chains of these 20 building blocks vary tremendously in size, shape,
and the presence of functional groups. They can be grouped as follows on
the basis of the chemical properties of the side chains: (1) hydrophobic side
chains—glycine, alanine, valine, leucine, isoleucine, methionine, proline as
well as the aromatic amino acids phenylalanine and tryptophan; (2) polar
amino acids—serine, threonine, tyrosine, asparagine and glutamine;
(3) positively charged amino acids—lysine, arginine, and histidine; and
(4) negatively charged amino acids—aspartic acid and glutamic acid.
3.3
Essential Amino Acids Must Be Obtained from the Diet
Most microorganisms are capable of making all 20 of the amino acids from
simpler molecules. Although human beings can make 11 amino acids, 9
must be acquired from the diet. These 9 amino acids are called essential
amino acids because they are required for healthy growth and development.
Key Terms
side chain (R group) (p. 33)
amino acid (p. 33)
dipolar ion (zwitterion) (p. 33)
essential amino acids (p. 39)
L
Answer to QUICK QUIZ
Lysine, arginine, and histidine are positively charged at neutral pH. Three amino acids containing hydroxyl groups are
serine, threonine, and tyrosine.
Problems
1. Hidden message. Translate the following amino acid
sequence into one-letter code: Glu-Leu-Val-Ile-Ser-Ile-SerLeu-Ile-Val-Ile-Asn-Gly-Ile-Asn-Leu-Ala-Ser-Val-Glu-GlyAla-Ser.
2. Identify. Examine the following four amino acids:
What are their names, three letter abbreviations, and oneletter symbols?
+
H2N
CH
+
CH
H3N
+
H3N
CH2
CH2
H2C
COO–
COO–
COO–
CH2
CH
COO–
+
H3N
CH
CH2
CH2
CH
CH2
CH3
H3C
CH2
CH2
OH
+
NH3
A
B
C
D
Problems
3. Properties. In reference to the amino acids shown
in problem 2, which are associated with the following
characteristics:
(a) Hydrophobic side chain _____
(b) Basic side chain _____
(c) Three ionizable groups _____
(d) pKa of approximately 10 in proteins _____
(e) Modified form of phenylalanine _____
4. Match ’em. Match each amino acid in the left-hand column with the appropriate side-chain type in the right-hand
column.
(a) Leu
(1) hydroxyl-containing
(b) Glu
(2) acidic
(c) Lys
(3) basic
(d) Ser
(4) sulfur-containing
(e) Cys
(5) nonpolar aromatic
(f) Trp
(6) nonpolar aliphatic
41
5. Solubility. In each of the following pairs of amino acids,
identify which amino acid would be most soluble in water:
(a) Ala, Leu; (b) Tyr, Phe; (c) Ser, Ala; (d) Trp, His.
6. Bonding is good. Which of the following amino acids
have R groups that have hydrogen-bonding potential? Ala,
Gly, Ser, Phe, Glu, Tyr, Ile, and Thr.
7. Minor species. For an amino acid such as alanine, the
major species in solution at pH 7 is the zwitterionic form.
Assume a pKa value of 8 for the amino group and a pKa
value of 3 for the carboxylic acid. Estimate the ratio of the
concentration of the neutral amino acid species (with the
carboxylic acid protonated and the amino group neutral) to
that of the zwitterionic species at pH 7.