A. The amino acids are the building blocks of proteins.

1. The 20 amino acids that cells use to make proteins have a

common core structure.
1. Most amino acids have a central carbon atom to which is
attached a hydrogen atom, an amino group, NH3 +, and a
carboxyl group, COO.
2. The side chain or R group distinguishes each amino acid
chemically.
2. Assembly of the amino acids to form peptides and proteins occurs
by stepwise fusion of the carboxyl group of one amino acid with
the amino group of another, with loss of a molecule of water during
the reaction to form a peptide bond.
3. Proteins can have a broad diversity of structures depending on
their amino acid sequences and composition.
4. The central carbon and the atoms involved in end-to-end linkage of
the amino acids form the polypeptide backbone, with the side
chains protruding outwardly to interact with other parts of the
protein or with other molecules.
B. The 20 common amino acids can be classified into groups
with similar side chain chemistry.
1. The nonpolar or hydrophobic amino acidsglycine, alanine, valine,
leucine, and isoleucinehave alkyl side chains (or simply a
hydrogen atom in the case of glycine).
2. Serine and threonine are small, polar amino acids that have
hydroxyl groups.
3. The sulfur-containing amino acids are cysteine and methionine.
4. The aromatic amino acids, phenylalanine, tyrosine, and tryptophan,
have ring structures and are nonpolar with the exception of the
hydroxyl group of tyrosine.
5. The acidic amino acids, aspartic acid and glutamic acid, have
carboxyl groups.
6. The amides of the carboxylic amino acids, asparagine and
glutamine, are uncharged and polar.
7. Members of the basic group, histidine, lysine, and arginine, have
weak-base side chains.
8. Proline is unique; it is an imino acid because its side chain loops
back to form a five-membered ring with its amino group, which
causes proline to produce kinks in the polypeptide backbone.
The pH at which an amino acid, a peptide,
or a protein has zero overall chargeafter
summing the contributions of all the charges
is called the isoelectric point (pI).
1. When pH < pI, the overall charge is positive.
2. When pH > pI, the overall charge is negative.
3. When pH = pI, there is no overall charge. A
peptide or protein in such a case would not
move in an electric field applied during
electrophoresis.
A. Primary structure refers to the linear sequence of amino acids linked by
peptide bonds to make up a protein.
B. Secondary structure describes the twisting of the polypeptide backbone
into regular structures that are stabilized by hydrogen bonding.
1. The -helix is a coiled structure stabilized by intrastrand hydrogen
bonds
1. The structure is both extensible and springy, which contributes to
the function of proteins that are primarily -helix, such as
keratins of fingernails, hair, and wool.
2. Amino acid side chains project outward, away from the axis of
the -helix and decorate its exterior surface.
2. Sheet structures are made from highly extended polypeptide chains
that link together by hydrogen bonds between the neighboring
strands and can be oriented in parallel or anti parallel arrays.
1. Due to the very extended conformation of the polypeptide
backbone, -sheets resist stretching.
2. The amino acid side chains project on either side of the plane of
a -sheet.
3. Silk is composed of the protein fibroin, which is entirely -sheet.
C. Tertiary structure is formed by combinations of
secondary structural elements into a three-dimensional
organization that is mainly stabilized by noncovalent
interactions, such as hydrogen bonds.
1. Protein folding is the complex process by which tertiary
structures form within the cell.
2. Regions of proteins that are capable of folding independently
and that often have distinct functions are called domains.
3. The side chains of highly polar amino acids tend to reside on
the exterior of proteins, where they can form hydrogen bonds
with water.
4. The side chains of nonpolar amino acids are normally clustered
in the interior of proteins to shield them from water.
D. Quaternary structure occurs in proteins that have
multiple polypeptide chains, called subunits.
1. In most cases, as in hemoglobin, the subunits are held together
by noncovalent interactions.
2. In some multisubunit proteins, such as immunoglobulins, the
subunits are held together by disulfide bonds or other covalent
interactions.
A. Collagen is an abundant protein that provides the structural
framework for tissues and organs.
1. The long rod-like shape of collagen provides rigidity and
strength to support the architecture of organs and tissues and
to make connective tissue.
2. Procollagen chains undergo extensive modification that
strengthens the mature collagen molecules.
B. Collagen is composed of three highly extended chains that wrap
around each other tightly in a triple helix
1. Collagen is high in glycine, proline, and the modified amino
acids hydroxyproline and hydroxylysine.
2. Every third amino acid in most collagen chains is glycine, in
triplet repeats of the sequence Gly-Pro-X and Gly-X-
hydroxyproline, where X = any amino acid.
3. The high frequency of glycine, with its small side chain, allows
the three collagen chains to pack very tightly together for
strength.
4. Hydrogen bonding between the chains further stabilizes the
triple helix.
C. Much of collagens strength arises from the
special mechanism of its synthesis, post-
translational modification, and assembly into
collagen fibers.
1. Covalent cross-linking of collagen chains adds
markedly to the strength of the triple helix as well as
to the larger structures formed by these
connections.
a. The first step in cross-linking is post-translational
modification of some lysine residues in collagen to allysine,
catalyzed by the enzyme lysyl oxidase.
b. Allysine then reacts spontaneously with nearby lysine
amino groups to form the cross-link.
2. The final steps of collagen post-translational
modification, including assembly of collagen fibrils
and collagen fibers, occur after the protein has been
secreted from the cell.
A. Myoglobin is the primary oxygen (O2) storage protein in muscle,
where it binds O2 with high affinity.
1. The heme group is held in a hydrophobic crevice of myoglobin and is
made up of a porphyrin ring that forms four coordinate covalent bonds
with the Fe2+ (ferrous iron) in its center.
2. In addition to interactions with the porphyrin ring, the heme Fe2+ is
bonded to two histidine residues of the protein; when oxygen binds to
the Fe2+, it displaces the distal histidine.
3. O2 remains bound until the PO2 in muscle is very low (< 5 mm Hg), eg,
during intensive exercise, which causes O2 to dissociate so that it can
be used in aerobic metabolism.
B. Hemoglobin in RBCs is responsible for O2 transport from the
lungs to the tissues for use in metabolism.
1. Hemoglobin binds O2 at the high PO2 (100 mm Hg) of the lung
capillary beds and transports it to the peripheral tissues, where PO2 is
lower (~30 mm Hg) and O2 dissociates from hemoglobin.
2. Adult hemoglobin (HbA) is a heterotetramer of two and two
subunits, each of which has a protein component called globin that
has a structure similar to myoglobin. Each subunit also has a heme
group with a Fe2+ atom at its center.
3. The hemoglobin heterotetramer is really a dimer of
dimers, in which two halves of the heterotetramer
are held together at their interface by noncovalent
interactions.
4. Fetal hemoglobin (HbF), which has slightly different
O2 binding properties from HbA, is composed of two -
and two -globin subunits.
a. HbF has a higher affinity for O2 at all PO2 values than HbA,
which facilitates transplacental transfer of O2 from maternal
blood to the fetal circulation.
b. Switchover from expression of HbF to HbA occurs within 6
months of birth due to progressive shutdown of genes
encoding the -globin chains and coordinate up-regulation of
the genes for -globin.
5. There is no counterpart to the distal histidine of
myoglobin in hemoglobin.
a. The Fe2+, which prefers six ligands, is coordinately bonded in
hemoglobin at four positions by the porphyrin ring and in a fifth
position by one histidine from the protein, with the sixth position
being unfilled until O2 binds.
b. The five-liganded condition of the Fe2+ in hemoglobin distorts
its structure and is important in initiating the conformational
change that occurs on O2 binding.
6. The O2 saturation curve of hemoglobin is different from that of
myoglobin (Figure 25), with increasing affinity of hemoglobin for
O2 as O2 loading increases, indicating cooperativity of O2
binding.
7. Hemoglobin alternates between two structurally and functionally
distinct forms to fulfill its physiologic role.
a. Deoxyhemoglobin, in which all four O2 binding sites are unoccupied
and which is also called the T or taut form, has low O2 affinity.
b. Oxyhemoglobin, to which four O2 molecules are bound and which is
also called the R or relaxed form, has high O2 affinity.
8. Although the structure of deoxyhemoglobin resists loading of O2,
this resistance is overcome in the lungs by high PO2.
a. Binding of O2 to the heme Fe2+ of one of the subunits causes a
conformational change in the protein near the heme group that
results from altered orientation of the Fe2+ in the plane of the porphyrin
ring and a corresponding shift of the nearby protein structure.
b. This small shift is propagated through the protein backbone to force
reorganization of noncovalent interactions at the dimer interface; some
hydrogen bonds and salt bridges break and new ones characteristic of
oxyhemoglobin are made.
c. In this way, the changes in structure of the subunit to which O2 is
bound are transmitted to the other subunits, each of which increases its
affinity for and then binds O2.
9. Conditions in the peripheral tissues that stabilize the structure
of deoxyhemoglobin promote dissociation of O2.
a. CO2 arising from metabolism must be carried back to the lungs for
respiration and 1015% is transported by covalent attachment to the
aminoterminal ends of some of the hemoglobin subunits.
b. The majority of CO2 combines with water in a reaction catalyzed by
carbonic anhydrase to form carbonic acid, which dissociates to
bicarbonate and a proton, which is taken up by amino groups on
hemoglobin.
c. By altering noncovalent interactions between the dimers, both of
the above effects favor conversion of hemoglobin from the oxy form to
the deoxy form and, in so doing, enhance dissociation of O2 from
oxyhemoglobin in the tissues.
d. The Bohr effect is the tendency of hemoglobin to release O2 in
response to decreased pH, conditions that prevail in metabolically
active tissues.
1) Binding of protons to critical groups on hemoglobin stabilizes
deoxyhemoglobin and thereby decreases the O2 binding affinity of
hemoglobin.
2) Conversely, increasing the pH promotes dissociation of protons from these
groups on hemoglobin and favors return to the high-affinity state.
10.10. A byproduct of glycolysis, 2,3-
bisphosphoglycerate (BPG) is present in the
RBCs at nearly equal concentration to that of
hemoglobin, and it is a key regulator of O2
affinity.
a. BPG binds by making salt bridges with several
positively charged residues in the hemoglobin
central cavity; this cavity is large enough to
accommodate BPG in deoxyhemoglobin but is too
small for BPG to fit in oxyhemoglobin.
b. BPG binding drives the oxy-to-deoxy conversion of
hemoglobin and so promotes O2 dissociation to
facilitate delivery of O2 to the tissues, where the PO2
is low.
c. In the lungs, PO2 is high enough to force loading of
O2 to nearly saturate hemoglobin even in the
presence of BPG.
d. HbF does not bind BPG, which gives HbF a higher
affinity for O2 than HbA.
A. Antibodies or immunoglobulins (Ig) are produced by B lymphoid cells
in response to the presence of foreign molecules, usually proteins,
nucleic acids, or carbohydrates, which are called antigens.
1. Most antibodies have a complex quaternary structure, being
composed of four individual polypeptide chains, two heavy (H)
chains and two light (L) chains.
2. The polypeptide chains are held together by disulfide bonds
between the H and L chains within each half-molecule and between
the H chains that join at the hinge region.
B. Diversity in the abilities of antibodies to recognize various antigens
arises from differences in primary structure in the antigen-binding or
variable region.
1. The differences in sequence within the variable region produce a
practically unlimited number of possible three-dimensional
arrangements for the amino acid side chains to form the
complementarity-determining region (CDR), which actually binds
to the antigen.
2. Antigen binding by the CDR occurs through noncovalent
interactions that allow antibodies to be specific for structurally
distinct antigens.
C. Antibodies are divided into five classes based
on their constant regions and immune
function.
1. IgM molecules are the first to appear after antigen
exposure and are unique in that they are made up of
five antibody molecules coupled into a large array by
disulfide bonding.
2. IgG molecules are the most abundant in plasma
and represent the main line of defense in the
immune response.
3. IgA molecules are secreted by and present in
mucous membranes lining the intestine and the
upper respiratory tract as well as in tears and the
breast secretions milk and colostrum.
4. The normal function of IgD molecules is not known.
5. IgE molecules mediate the allergic response.