590
chapter 25
RNA and Protein Synthesis
limited to skin. The animal counterpart of lysyl oxidase
deficiency is seen in several variants of aneurysm-prone
mice. All of these disorders are X-linked.
Lysyl
oxidase
undergoes
irreversible
inactivation
when exposed to certain nitriles. /LAminopropionitrile
(H
2
N-CH
2
-CH
2
-CN), which is found in certain peas
(e.g.,
Lathyrus odoratus),
inhibits the lysyl oxidase pre-
sumably by binding covalently to the enzyme. Ingestion
of these peas results in
lathyrism,
which is characterized
by multiple defects in collagen- and elastin-containing
tissues. In experimental animals, lathyrism is produced
by administering /Laminopropionitrilc during their active
growth period. Lysyl oxidase is also irreversibly inhibited
by carbonyl reagents (e.g., hydroxylamine) and copper-
chelating agents.
Impaired cross-linking can also occur as a result of cop-
per deficiency, since lysyl oxidase is a copper-dependent
enzyme. In experimental animals, copper deprivation
causes skeletal and cardiovascular abnormalities. These
abnormalities are similar to a human disorder known as
Marfan’s syndrome,
an autosomal dominant trait whose
molecular defect is unknown. A genetic defect affect-
ing the gastrointestinal absorption of copper, known as
Menkes
’
(kinky-hair) syndrome,
exhibits neurological,
connective tissue, pigmentary, and hair abnormalities.
These defects can be explained by deficient activities of
various copper-requiring enzymes (Chapter 37). The con-
nective tissue changes are attributed to the deficiency of
lysyl oxidase.
Cross-linking can be inhibited by agents that can react
with the aldehyde groups of allysyl and hydroxyllysine
residues. Penicillamine reacts with the aldehyde groups,
forming a thiazolidine complex and rendering the alde-
hyde groups unavailable for cross-link formation.
H
3
C
H S — c
H
2
N— CH
I
C O O H
P e n ic illa m in e
H 3C
C H
3
T h ia z o lid in e
c o m p le x
Penicillamine is an effective chelator of copper, thereby
inhibiting lysyl oxidase. Penicillamine is used therapeuti-
cally in the treatment of disorders involving copper ac-
cumulation (
Wilson’s disease
) or in lead and mercury
poisoning.
Several inherited disorders of methionine metabolism
(Chapter 17) give rise to excessive production of homocys-
teine, HS-CH
2
-CH
2
CH(NH^)COO_, and its excretion in
urine. The most common form of
homocystinuria
is due
to a deficiency of cystathionine synthase (Chapter 17).
A major clinical manifestation of homocystinuria is con-
nective tissue abnormalities that are probably due to the
accumulation of homocysteine, which either inactivates
the reactive aldehyde groups or impedes the formation of
polyfunctional cross-links.
The structure or the metabolism of collagen is abnor-
mal in a variety of other disorders. For example, in
dia-
betes mellitus
(Chapter 22), poor wound healing, atrophy
of the skin, and thickening of the basement membranes
have been attributed to changes in collagen metabolism.
Fibrotic tissue and scars consist primarily of collagen fib-
rils. The fibrosis is a normal process of wound healing in
response to trauma and injury. However, excessive fibrosis
in parenchymal tissues (e.g., liver and lungs) can severely
limit their function. Thus, attempts are being made to de-
velop specific agents that would inhibit collagen synthesis
or increase its catabolism. Both growth and aging involve
changes in collagen metabolism. These changes occur in
the type, quantity, and quality of collagen. Growth of con-
nective tissues requires the appropriate type and amounts
of collagen. It is not known to what extent changes in
collagen metabolism are responsible for aging.
Supplemental Readings and References
N. Ban, P. Nissen, J. Hansen, et al.: The complete atomic structure
of the large ribosomal subunit at 2.4
A
Resolution.
S c i e n c e
289, 905
(
2000
).
P. Cramer, D. A. Bushnell, J. Fu, et at: Architecture of RNA polymerase
II and implications for the transcription mechanism.
S c i e n c e
288, 640
(
2000
).
D. E. Draper: Protein-RNA recognition.
A n n u a l R e v i e w s i n B i o c h e m i s t r y
64,593(1995).
L. Ellgaard, M. Molinari, and A. Helenius: Setting the standards: quality
control in the secretory pathway.
S c i e n c e
286, 1882 (1999).
R. Green and H. Noller: Ribosomes and translation.
A n n u a l R e v i e w s in
B i o c h e m i s t r y
6 6
, 40 (1997).
H. Guo, M. Karberg, M. Long, et al.: Group II introns designed to insert into
therapeutically relevant DNA target sites in human cells.
S c i e n c e
289,452
(
2000
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V. Hatzimanikatis, L. H. Choe, and K. H. Lee: Proteomics: theoretical and
experimental considerations.
B i o t e c h n o l o g y P r o g r e s s
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J. W. B. Hershey, M. B. Mathews, and N. Sonnenberg, eds.:
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