SECTION 6.4
Inhibition
103
TABLE 6-3
P rin cip a l P ro tein a se In h ib ito rs in H u m a n B lo o d P la sm a
*
Name
Concentration
(mg/100 mL)
Mol. Wt.
Number of
Polypeptide
Chains
Heads'
a
j
-Proteinase inhibitor
290±45
52,000
1
1
a
j
- Antichymotrypsin
49±7
69,000
1
1
Inter-a-trypsin inhibitor
50
160,000
1
2
« 2-Antiplasmin
7± 1
70,000
1
1
Antithrombin III
24±2
65,000
1
1
Cj-inactivator
24±3
70,000
1
1
a 2-Macroglobulin
260 ±70
720,000
4
1 - 2
or more
^Reproduced, with permission, from M. Lakowski, Jr., and I. Kato: Protein inhibitors of proteinases.
A n n u . R ev. B io c h e m .,
49,
593 (1980). © 1980
by Annual Reviews, Inc.
’•’Maximal number of enzyme molecules simultaneously inhibited by one inhibitor molecule.
proteinase inhibitors share significant homology at their
reactive site regions.
Neutrophils and macrophages function protectively
against foreign organisms in an inflammatory process.
In this process, a number of proteinases escape to sur-
rounding tissues. One such enzyme is elastase, which cat-
alyzes the hydrolysis of elastin, a protein of connective
tissue (Chapter 10). Normally, the activity of elastase is
inhibited by the
a \ -pro tein a se in h ib ito r
(also known as
a \-a n titry p sin ),
which inhibits a broad spectrum of pro-
teinases containing serine in their active sites (e.g., elas-
tase, trypsin, and chymotrypsin). Genetic deficiency of an
a
i -proteinase inhibitor strongly predisposes to pulmonary
emphysema and liver disease. Emphysema (which means
swelling or inflation) results from the breakdown of alve-
olar walls due to coalescence of alveoli resulting in for-
mation of air sacs, which leads to a gradual decrease in
the effectiveness of CO
2
elimination and oxygenation of
hemoglobin.
A
collection
of high-molecular-weight
proteinase
inhibitors
with
broad
specificity,
known
as
0
:
2
-
m acro g lo b u lin s,
are present in the plasma of all mam-
mals and exhibit an interesting inhibition pattern. When
«
2
-macroglobulins combine with a wide variety of pro-
teinases, they inhibit only the proteolytic activity of the
enzyme toward large protein substances without signif-
icantly affecting the catalysis of low-molecular-weight
substrates.
Proteinases and their inhibitors play a major role
in metastasis of cancer. Metastasis of tumors requires
remodeling of extracellular matrix (ECM). Remodeling is
a balance between proteolysis and respective proteinase
inhibitors. This process is aided by proteolytic enzymes
synthesized by the tumor cells. Examples of proteolytic
enzymes include serine proteinases, cathepsins, and ma-
trix metalloproteinases (Table 6-4). Some of the
ca th ep -
sin s
are cysteine proteinases and their inhibitors belong
to the cystatin superfamily. The
cysta tin fa m ily
consists
of three subfamilies:
stefins, cystatins,
and
rinogens.
Progressive loss of expression of the proteinase inhibitors
may be responsible for metastasis. The loss of control
over proteinase expression and their respective inhibitors
is influenced by a variety of biological response modifiers
such as growth factors, cytokines, tumor promoters, and
suppressor genes.
Viral proteinases (also called proteases) offer unique
targets for antiviral drugs. An example is in the treatment
of human immunodeficiency virus (HIV) infections by
HIV protease inhibitors (Figure 6-13). HIV is a retrovirus
and its RNA undergoes reverse transcription in cells to
produce double stranded DNA (Chapter 26). This step is
inhibited by nucleoside analogues such as zidovuline, di-
danosine, zalcitabine, stavudine, and lambivudine. The vi-
ral DNA, upon integration into the host genome, produces
a protease as well as polypeptides. The HIV protease is an
aspartyl protease and the enzymatic activity resides in the
homodimers. The HIV protease cleaves polypeptides at
phenylalanine-proline or tyrosine-proline bonds, which
are unusual sites of cleavage for mammalian proteases.
That cleavage results in the production of three large pro-
teins (p24, p i7, and p7) and three smaller proteins (p
6
,
p2, and p i). The three large proteins are essential for RNA
packaging and in the structure of the virion. Viral protease
is essential in the production of functionally mature and
infectious particles and thus is a prime target for inhibition
by drugs.
