Table Of ContentLip pin c o tt’s
Illu s tra te d Re v ie w s :
B io c h e m is t ry
S ixth Editio n
tahir99-VRG & vip.persianss.ir
Co nte nts
UNIT I: Protein Structure and Function
Chapter 1: Amino Acids 1
Chapter 2: Structure of Proteins 13
Chapter 3: Globular Proteins 25
Chapter 4: Fibrous Proteins 43
Chapter 5: Enzymes 53
UNIT II: Bioenergetics and Carbohydrate Metabolism
Chapter 6: Bioenergetics and Oxidative Phosphorylation 69
Chapter 7: Introduction to Carbohydrates 83
Chapter 8: Introduction to Metabolism and Glycolysis 91
Chapter 9: Tricarboxylic Acid Cycle and Pyruvate Dehydrogenase Complex 109
Chapter 10: Gluconeogenesis 117
Chapter 11: Glycogen Metabolism 125
Chapter 12: Metabolism of Monosaccharides and Disaccharides 137
Chapter 13: Pentose Phosphate Pathway and Nicotinamide Adenine Dinucleotide Phosphate 145
Chapter 14: Glycosaminoglycans, Proteoglycans, and Glycoproteins 157
UNIT III: Lipid Metabolism
Chapter 15: Dietary Lipids Metabolism 173
Chapter 16: Fatty Acid, Ketone Body, and Triacylglycerol Metabolism 181
Chapter 17: Phospholipid, Glycosphingolipid, and Eicosanoid Metabolism 201
Chapter 18: Cholesterol, Lipoprotein, and Steroid Metabolism 219
UNIT IV: Nitrogen Metabolism
Chapter 19: Amino Acids: Disposal of Nitrogen 245
Chapter 20: Amino Acid Degradation and Synthesis 261
Chapter 21: Conversion of Amino Acids to Specialized Products 277
Chapter 22: Nucleotide Metabolism 291
UNIT V: Integration of Metabolism
Chapter 23: Metabolic Effects of Insulin and Glucagon 307
Chapter 24: The Feed–Fast Cycle 321
Chapter 25: Diabetes Mellitus 337
Chapter 26: Obesity 349
Chapter 27: Nutrition 357
Chapter 28: Vitamins 373
UNIT VI: Storage and Expression of Genetic Information
Chapter 29: DNA Structure, Replication, and Repair 395
Chapter 30: RNA Structure, Synthesis, and Processing 417
Chapter 31: Protein Synthesis 431
Chapter 32: Regulation of Gene Expression 449
Chapter 33: Biotechnology and Human Disease 465
Appendix: Clinical Cas es 489
Index 522
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UN IT I:
Protein Str u ctu r e
an d Fu n ction
1
Am in o Ac id s
I. OVERVIEW
A
Free amino acid
Proteins are the most abundant and functionally diverse molecules
in living systems. Virtually every life process depends on this class of
These are common to
macromolecules. For example, enzymes and polypeptide hormones
all α-amino acids.
direct and regulate metabolism in the body, whereas contractile pro-
teins in muscle permit movement. In bone, the protein collagen forms a
framework for the deposition of calcium phosphate crystals, acting like CCCOOOOHH Carboxyl
group
the steel cables in reinforced concrete. In the bloodstream, proteins,
++
HH NN CCC HHH
αα
such as hemoglobin and plasma albumin, shuttle molecules essential 33
to life, whereas immunoglobulins fight infectious bacteria and viruses.
RRRR
AAmmiinnoo
In short, proteins display an incredible diversity of functions, yet all
ggrroouupp
share the common structural feature of being linear polymers of amino
acids. This chapter describes the properties of amino acids. Chapter 2
explores how these simple building blocks are joined to form proteins
Side chain α-Carbon is
that have unique three-dimensional structures, making them capable of is distinctive linked to the
for each amino carboxyl, amino,
performing specific biologic functions.
acid. and R groups.
B Amino acids combined
II. STRUCTURE
through peptide linkages
Although more than 300 different amino acids have been described
NH-CH-CO-NH-CH-CO
in nature, only 20 are commonly found as constituents of mammalian
proteins. [Note: These are the only amino acids that are coded for by RR RR
DNA, the genetic material in the cell (see p. 395).] Each amino acid
has a carboxyl group, a primary amino group (except for proline, which
has a secondary amino group), and a distinctive side chain (“R group”)
Side chains determine
bonded to the a -carbon atom (Figure 1.1A). At physiologic pH (approxi- properties of proteins.
mately 7.4), the carboxyl group is dissociated, forming the negatively
–
charged carboxylate ion (– COO ), and the amino group is protonated
Figure 1.1
+
(– NH ). In proteins, almost all of these carboxyl and amino groups
3
Structural features of amino acids
are combined through peptide linkage and, in general, are not avail-
(shown in their fully protonated form).
able for chemical reaction except for hydrogen bond formation (Figure
1.1B). Thus, it is the nature of the side chains that ultimately dictates
1
2 1. Amino Acids
the role an amino acid plays in a protein. It is, therefore, useful to clas-
sify the amino acids according to the properties of their side chains, that
is, whether they are nonpolar (have an even distribution of electrons)
or polar (have an uneven distribution of electrons, such as acids and
bases) as shown in Figures 1.2 and 1.3.
A. Amino acids with nonpolar s ide chains
Each of these amino acids has a nonpolar side chain that does not
gain or lose protons or participate in hydrogen or ionic bonds (see
Figure 1.2). The side chains of these amino acids can be thought
of as “oily” or lipid-like, a property that promotes hydrophobic inter-
actions (see Figure 2.10, p. 19).
1. Location of nonpolar amino acids in proteins : In proteins found
in aqueous solutions (a polar environment) the side chains of the
nonpolar amino acids tend to cluster together in the interior of the
protein (Figure 1.4). This phenomenon, known as the hydrophobic
NONPOLAR SIDE CHAINS
COOH pK = 2.3 COOH COOH
1
+H N C H +H N C H +H N C H
3 3 3
H CH CH
3
pK = 9.6
2 H C CH
3 3
Glycine Alanine Valine
COOH COOH COOH
+H N C H +H N C H +H N C H
3 3
3
CH H C CH
CH
2 3
2
CH CH
2
H C CH
3 3 CH
3
Leucine Isoleucine Phenylalanine
COOH COOH
+H3N C H +H N C H COOH
3
CH2 CH +H N C H
2 2
C CH H C CH
2 2 2
CH
CH S 2
N
H
CH
3
Tryptophan Methionine Proline
Figure 1.2
Classification of the 20 amino acids commonly found in proteins, according to the charge and polarity of their side
chains at acidic pH is shown here and continues in Figure 1.3. Each amino acid is shown in its fully protonated
form, with dissociable hydrogen ions represented in red print. The pK values for the α-carboxyl and α-amino
groups of the nonpolar amino acids are similar to those shown for glycine.
II. Structure of the Amino Acids 3
UUNNCCHHAARRGGEEDD PPOOLLAARR SSIIDDEE CCHHAAIINNSS
COOH pK = 2.2
1
++HH NN C H
33
COOH COOH
CH
2
+H N CC H ++HH NN CC H pK = 9.1
3 33 2
H CC OOHH HH CC OOHH
H CCHH
33
OH ppKK == 1100..11
33
Serine Threonine TTyyrroossiinnee
COOH COOH
++HH NN CC H ++HH NN CC H COOH pK1 = 1.7
33 33
CH CCHH +H N C H
2 22 3
CC CCHH CCHH
22 22
pK = 10.8
O NH2 CC 3 SH pK = 8.3
2
OO NNHH
22
Asparagine Glutamine Cysteine
AACCIIDDIICC SSIIDDEE CCHHAAIINNSS
pK = 2.1
1
COOH COOH
pK = 9.8 +H N C H pK = 9.7 +H N C H
3 3 3 3
CH CCHH
2 22
CC CH
2
OO OH ppKK == 33..99
22 CC
O OH pK = 4.3
2
Aspartic acid Glutamatic acid
BBAASSIICC SSIIDDEE CCHHAAIINNSS
pK = 1.8 pK = 2.2
1 1
ppKK == 99..22 pK = 9.2
33 2
pK = 9.0
2
COOH COOH COOH
++HH NN CC H ++HH NN CC H ++HH NN CC H
33 33 33
CCHH CCHH CCHH
22 22 22
CC CCHH CCHH CCHH
22 22
++HHNN NNHH CCHH CCHH
22 22
CC
HH CCHH NN HH
22
ppKK == 66..00 NNHH ++ ppKK == 1100..55 CC NNHH ++ ppKK == 1122..55
22 33 33 22 33
NNHH
22
Histidine Lysine Arginine
Figure 1.3
Classification of the 20 amino acids commonly found in proteins, according to the charge and polarity
of their side chains at acidic pH (continued from Figure 1.2).
4 1. Amino Acids
effect, is the result of the hydrophobicity of the nonpolar R groups,
which act much like droplets of oil that coalesce in an aqueous
Nonpolar amino Nonpolar amino
acids ( ) cluster acids ( ) cluster
environment. The nonpolar R groups, thus, fill up the interior of
in the interior of on the surface of
the folded protein and help give it its three-dimensional shape.
soluble proteins. membrane proteins.
However, for proteins that are located in a hydrophobic environ-
ment, such as a membrane, the nonpolar R groups are found on
the outside surface of the protein, interacting with the lipid environ-
ment see Figure 1.4. The importance of these hydrophobic interac-
tions in stabilizing protein structure is discussed on p. 19.
CCeellll
membrane
Sickle cell anemia, a sickling disease of red blood
Polar amino acids
( ) cluster on cells, results from the replacement of polar gluta-
the surface of
mate with nonpolar valine at the sixth position in
soluble proteins.
the b subunit of hemoglobin (see p. 36).
Soluble protein Membrane protein
Figure 1.4
2. Proline: Proline differs from other amino acids in that its side
Location of nonpolar amino acids
in soluble and membrane proteins. chain and a -amino N form a rigid, five-membered ring structure
(Figure 1.5). Proline, then, has a secondary (rather than a pri-
mary) amino group. It is frequently referred to as an “imino acid.”
The unique geometry of proline contributes to the formation of the
Secondary amino Primary amino
fibrous structure of collagen (see p. 45) and often interrupts the
group group
a -helices found in globular proteins (see p. 26).
COOH
COOH
B. Amino acids with uncharged polar s ide chains
+H2N C H +H N C H
3
These amino acids have zero net charge at physiologic pH, although
H C CH
2 2 CH3 the side chains of cysteine and tyrosine can lose a proton at an
CH
2
alkaline pH (see Figure 1.3). Serine, threonine, and tyrosine each
Proline Alanine
contain a polar hydroxyl group that can participate in hydrogen bond
formation (Figure 1.6). The side chains of asparagine and glutamine
Figure 1.5
each contain a carbonyl group and an amide group, both of which
Comparison of the secondary
can also participate in hydrogen bonds.
amino group found in proline with
the primary amino group found
in other amino acids such as 1. Dis ulfide bond: The side chain of cysteine contains a sulfhydryl
alanine.
(thiol) group (–SH), which is an important component of the active
site of many enzymes. In proteins, the –SH groups of two cysteines
can be oxidized to form a covalent cross-link called a disulfide bond
COOH
(–S–S–). Two disulfide-linked cysteines are referred to as “cystine.”
+H N C H
3
(See p. 19 for a further discussion of disulfide bond formation.)
CH
2
Tyrosine
Ma ny e xtra ce llula r prote ins a re s ta bilize d by
O disulfide bonds. Albumin, a blood protein that
functions as a transporter for a variety of mol-
H
Hydrogen ecules, is an example.
bond
O
Carbonyl
group
C
2. Side chains as s ites of attachment for other compounds : The
polar hydroxyl group of serine; threonine; and, rarely, tyrosine, can
Figure 1.6
serve as a site of attachment for structures such as a phosphate
Hydrogen bond between the
group. In addition, the amide group of asparagine, as well as the
phenolic hydroxyl group of tyrosine
hydroxyl group of serine or threonine, can serve as a site of attach-
and another molecule containing a
ment for oligosaccharide chains in glycoproteins (see p. 165).
carbonyl group.
II. Structure of the Amino Acids 5
C. Amino acids with acidic s ide chains
1
Unique firs t letter:
The amino acids aspartic and glutamic acid are proton donors. At
physiologic pH, the side chains of these amino acids are fully ionized,
Cysteine = Cys = C
containing a negatively charged carboxylate group (–COO–). They Histidine = His = H
Isoleucine = Ile = I
are, therefore, called aspartate or glutamate to emphasize that these
Methionine = Met = M
amino acids are negatively charged at physiologic pH (see Figure 1.3).
Serine = Ser = S
Valine = Val = V
D. Amino acids with bas ic s ide chains
Mos t commonly occurring
The side chains of the basic amino acids accept protons (see Figure 2
amino acids have priority:
1.3). At physiologic pH, the R groups of lysine and arginine are fully
ionized and positively charged. In contrast, histidine is weakly basic, Alanine = Ala = A
Glycine = Gly = G
and the free amino acid is largely uncharged at physiologic pH.
Leucine = Leu = L
However, when histidine is incorporated into a protein, its R group
Proline = Pro = P
can be either positively charged (protonated) or neutral, depending
Threonine = Thr = T
on the ionic environment provided by the protein. This is an impor-
tant property of histidine that contributes to the buffering role it plays
3
in the functioning of proteins such as hemoglobin (see p. 31). [Note: Similar s ounding names :
Histidine is the only amino acid with a side chain that can ionize
Arginine = Arg = R (“aRginine”)
within the physiologic pH range.]
Asparagine = Asn = N (contains N)
Aspartate = Asp = D ("asparDic")
E. Abbreviations and s ymbols for commonly occurring amino acids
Glutamate = Glu = E ("glutEmate")
Glutamine = Gln = Q (“Q-tamine”)
Each amino acid name has an associated three-letter abbrevia-
Phenylalanine = Phe = F (“Fenylalanine”)
tion and a one-letter symbol (Figure 1.7). The one-letter codes are
Tyrosine = Tyr = Y (“tYrosine”)
determined by the following rules.
Tryptophan = Trp = W (double ring in
the molecule)
1. Unique firs t letter: If only one amino acid begins with a given letter,
4
then that letter is used as its symbol. For example, V = valine. Letter clos e to initial letter:
2. Mos t commonly occurring amino acids have priority: If more
Aspartate or = Asx = B (near A)
than one amino acid begins with a particular letter, the most com- asparagine
Glutamate or = Glx = Z
mon of these amino acids receives this letter as its symbol. For
glutamine
example, glycine is more common than glutamate, so G = glycine.
Lysine = Lys = K (near L)
Undetermined = X
3. Similar s ounding names : Some one-letter symbols sound like the
amino acid
amino acid they represent. For example, F = phenylalanine, or
W = tryptophan (“twyptophan” as Elmer Fudd would say).
Figure 1.7
4. Letter clos e to initial letter: For the remaining amino acids, a one-
Abbreviations and symbols for the
letter symbol is assigned that is as close in the alphabet as pos- commonly occurring amino acids.
sible to the initial letter of the amino acid, for example, K = lysine.
Furthermore, B is assigned to Asx, signifying either aspartic acid
or asparagine, Z is assigned to Glx, signifying either glutamic acid
or glutamine, and X is assigned to an unidentified amino acid.
H
O H
O O
C O
F. Optical properties of amino acids C
H
H
C
N C
The a -carbon of an amino acid is attached to four different chemical +H3 H H NH +
C 3 C 3
3
gcarorbuopns (aatsoymm. mGelytrcicin) ea nisd thise, tehxecreepfotiroen, ab ecchairuasl,e oirt so apt-iccaarllbyo nac htiaves L-Alanine D-Alanine
two hydrogen substituents. Amino acids with an asymmetric center
at the a -carbon can exist in two forms, designated D and L, that are
mirror images of each other (Figure 1.8). The two forms in each
Figure 1.8
pair are termed stereoisomers, optical isomers, or enantiomers. All
and forms of alanine
D L
amino acids found in proteins are of the configuration. However,
l are mirror images.
D-amino acids are found in some antibiotics and in bacterial cell
walls. (See p. 252 for a discussion of D-amino acids.)
6 1. Amino Acids
III. ACIDIC AND BASIC PROPERTIES OF AMINO ACIDS
Amino acids in aqueous solution contain weakly acidic a -carboxyl
groups and weakly basic a -amino groups. In addition, each of the
acidic and basic amino acids contains an ionizable group in its side
chain. Thus, both free amino acids and some amino acids combined in
peptide linkages can act as buffers. Recall that acids may be defined
as proton donors and bases as proton acceptors. Acids (or bases)
described as “weak” ionize to only a limited extent. The concentration of
+
protons in aqueous solution is expressed as pH, where pH = log 1/[H ]
+
or – log [H ]. The quantitative relationship between the pH of the solu-
–
tion and concentration of a weak acid (HA) and its conjugate base (A )
is described by the Henderson-Hasselbalch equation.
OH– H O A. Derivation of the equation
2
– Consider the release of a proton by a weak acid represented by HA:
CH COOH CH COO
3 3
FORM I FORM II
+ ← + –
H – HA H + A
(acetic acid, HA) (acetate, A ) →
weak proton salt form
acid or conjugate base
Buffer region
[II] > [I]
–
The “salt” or conjugate base, A , is the ionized form of a weak acid.
1.0
By definition, the dissociation constant of the acid, K , is
d a
e
d
d
a + –
[H ][A ]
–
H K
[I] = [II] pK = 4.8
O a a [HA]
0.5
s
t
n
e
l
a [Note: The larger the K , the stronger the acid, because most of the
v a
i
u + –
HA has dissociated into H and A . Conversely, the smaller the K ,
q
a
E [I] > [II]
the less acid has dissociated and, therefore, the weaker the acid.]
0
+
0 3 4 5 6 7 By solving for the [H ] in the above equation, taking the logarithm of
pH both sides of the equation, multiplying both sides of the equation by
+
–1, and substituting pH = – log [H ] and pK = – log K , we obtain
a a
Figure 1.9 the Henderson-Hasselbalch equation:
Titration curve of acetic acid.
–
[A ]
pH pK + log
a
[HA]
B. Buffers
A buffer is a solution that resists change in pH following the addition of
an acid or base. A buffer can be created by mixing a weak acid (HA)
–
with its conjugate base (A ). If an acid such as HCl is added to a buf-
–
fer, A can neutralize it, being converted to HA in the process. If a base
–
is added, HA can neutralize it, being converted to A in the process.
Maximum buffering capacity occurs at a pH equal to the pK , but a con-
a
jugate acid–base pair can still serve as an effective buffer when the pH
of a solution is within approximately ±1 pH unit of the pK . If the amounts
a
–
of HA and A are equal, the pH is equal to the pK . As shown in Figure
a
III. Acidic and Basic Properties of Amino Acids 7
– –
OH H O OH H O
2 2
– –
COOH COO COO
+
H N C H +H N C H H N C H
3 3 2
CH CH CH
3 3 3
+ +
H H
FORM I FORM II FORM III
pK = 2.3 pK = 9.1
1 2
Alanine in acid solution Alanine in neutral solution Alanine in basic solution
(pH less than 2) (pH approximately 6) (pH greater than 10)
Net charge = +1 Net charge = 0 Net charge = 1
–
(isoelectric form)
Figure 1.10
Ionic forms of alanine in acidic, neutral, and basic solutions.
1.9, a solution containing acetic acid (HA = CH – COOH) and acetate
3
– –
(A = CH – COO ) with a pK of 4.8 resists a change in pH from pH 3.8
3 a
to 5.8, with maximum buffering at pH 4.8. At pH values less than the
pK , the protonated acid form (CH – COOH) is the predominant species
a 3
in solution. At pH values greater than the pK , the deprotonated base
a
–
form (CH – COO ) is the predominant species.
3
C. Titration of an amino acid
1. Dis s ociation of the carboxyl group: The titration curve of an
amino acid can be analyzed in the same way as described for
acetic acid. Consider alanine, for example, which contains an
ionizable a -carboxyl and a -amino group. [Note: Its –CH R group
3
is nonionizable.] At a low (acidic) pH, both of these groups are
protonated (shown in Figure 1.10). As the pH of the solution is
raised, the – COOH group of form I can dissociate by donating a
proton to the medium. The release of a proton results in the for-
–
mation of the carboxylate group, – COO . This structure is shown
as form II, which is the dipolar form of the molecule (see Figure
1.10). This form, also called a zwitterion, is the isoelectric form of
alanine, that is, it has an overall (net) charge of zero.
2. Application of the Henders on-Has s elbalch equation: The dissoci-
ation constant of the carboxyl group of an amino acid is called K ,
1
rather than K , because the molecule contains a second titratable
a
group. The Henderson-Hasselbalch equation can be used to ana-
lyze the dissociation of the carboxyl group of alanine in the same
way as described for acetic acid:
+
[H ][II]
K
1
[I]
where I is the fully protonated form of alanine, and II is the iso-
electric form of alanine (see Figure 1.10). This equation can be
rearranged and converted to its logarithmic form to yield:
