Inhibitors o f Protein Synthesis in Eukaryotes
Inhibits binding of aminoacyl
Catalyzes a reaction between
NAD* and EF2 to yield an
inactive factor. Inhibits
Inhibits peptydyltransferase of
mitochondrial ribosomes. Is
inactive against cytoplasmic
Causes premature chain
termination by acting as an
analogue of charged tRNA.
Inhibits translocation by altering
an elongation factor.
Inhibits positioning of tRNA'let
on the 40S ribosome.
Inhibits formation of the
*Also active on prokaryotic ribosomes.
polypeptide chains with two different but complementary
functions. The A chain possesses enzymatic activity and is
responsible for toxicity, and the B chain, which is a lectin,
binds to galactose-containing glycoproteins or glycolipids
on the cell surface. The A and B chains are linked by a la-
bile disulfide linkage. Upon binding of the ricin molecule
to the carbohydrate receptors of the cell surface via the
B chain, the A chain enters the cytoplasm, presumably by
receptor-mediated endocytosis, where it inhibits protein
synthesis by irreversible inactivation of the 60S ribosomal
subunit. Toxins have been used to develop highly selective
cytotoxic agents targeted against specific cells. For exam-
ple, ricin A has been coupled to agents that selectively
bind to cell surface membrane components. The selec-
tive agents may be monoclonal antibodies (Chapter 35),
hormones, or other cell surface ligands. These conjugates
act as selective cytotoxic agents and may have potential
therapeutic applications (e.g., in the treatment of cancer).
Potential clinical application for diphtheria toxin may be
impossible because of the prevalence of the diphtheria
antitoxin in human populations.
Collagen Biosynthesis and Its Disorders
Collagen occurs in several genetically distinct forms and
is the most abundant body protein; most of the body scaf-
folding is composed of collagen (Chapter 11). Its structure
is uniquely suited for this structural role. It is a fibrillar pro-
tein but also exists in a nonfibrillar form in the basement
membrane. The basic structural unit of collagen,
consists of three polypeptide chains. Each polypep-
tide chain has the general formula (-Gly-X-Y->
3 3 3
of the amino acid residues at the X and Y positions are pro-
line, hydroxyproline, lysine, hydroxylysine, and alanine.
Collagen is a glycoprotein and contains only two types
of carbohydrate residues, namely, glucose and galactose
linked in O-glycosidic bonds to hydroxylysyl residues.
In collagen, each polypeptide chain is coiled into a
special type of a rigid, kinked, left-handed helix, with
about three amino acid residues per turn. The three he-
lical polypeptides in turn are wrapped around each other
to form a right-handed triple-stranded superhelix that is
stabilized by hydrogen bonding. The collagen molecules
are aggregated in an ordered quarter-staggered array to
give rise to microfibrils, which in turn combine to give
fibrils. Covalent cross-linkages occur at various levels of
collagen fiber organization and provide great mechanical
strength. Collagen biosynthesis is unusual in that it con-
sists of many posttranslational modifications. The unique
posttranslational reactions of collagen biosynthesis are
1. Hydroxylation of selected prolyl and lysyl residues.
2. Glycosylation of certain hydroxylysyl residues.
3. Folding of procollagen polypeptides into a triple
4. Conversion of procollagen to collagen.
5. Self-assembly into fibrils.
. Oxidative deamination of e-amino groups of
strategically located lysyl and hydroxylysyl residues
to provide reactive aldehydes. These form
cross-linkages between polypeptide chains of the
same molecule as well as between the adjacent
molecules that give strength and stability to the fibrils.
The first three processes take place inside the cell, whereas
the last three are extracellular modifications.
Collagen disorders can result from primary defects in
the structure of procollagen or collagen or from secondary
changes that affect collagen metabolism. Collagen dis-
orders are both acquired and inherited.
are examples of
inherited primary collagen diseases;
fibrotic processes (e.g., pulmonary fibrosis and cirrhosis)