Plasminogen - Chromogenix

NH 2
Plasminogen, version 1.1
F
NH 2
EGF
EGF
46
Single-chain t-PA is a 68 kDa glycoprotein,
consisting of 530 amino acids and containing 7-13%
carbohydrate. In human plasma, t-PA occurs mainly
as a complex together with its principal inhibitor
PAI-1. The level of t-PA antigen is about 5 μg/ml,
whereas the concentration of free t-PA is only about
1 μg/l or 0.5 IU/ml (specific activity range 500,000
to 700,000 U/mg). The single-chain t-PA molecule is
converted by plasmin to a two-chain form by cleavage
of the Arg 275 -Ile 276 peptide bond. Binding to
fibrin concentrates and correctly orientates t-PA and
plasminogen, as well as inducing conformational
changes in the molecules that promote efficient clot
lysis.
Urokinase
275
K1 K2 P
158
K1
156
P
Urokinase-type plasminogen activator (u-PA) is
mainly produced in the kidneys as an inactive
single-chain molecule (scu-PA). u-PA has its major
function in tissue-related proteolysis and is believed
to play only a secondary role to t-PA as a physiological
activator in blood.
The activation of scu-PA by catalytic amounts of
plasmin results in a two-chain structure with increased
activity towards plasminogen. Through this
mechanism, initial traces of plasmin may catalyze
the production of active u-PA, leading to the formation
of more plasmin. u-PA can only activate plasminogen
in the presence of fibrin. However, it does
135
143
COOH
411
Biochemistry
COOH
530
7
Figure 3. Domain structures of t-PA and u-PA.
The t-PA molecule is composed of at least five domains: a finger
domain, the epidermal growth factor domain (EGF), two kringle
domains and the protease domain. The u-PA molecule consists
of a EGF domain, one kringle and the protease domain. The
finger domain is homologous to structures found in fibronectin.
In the t-PA molecule this domain is implicated with fibrin
binding. The EGF domain often confers affinity to specific
receptors on cell surfaces.
not bind to fibrin and is not activated by fibrin. In
human plasma, u-PA antigen concentrations range
from 2 to 7 ng/ml. Higher values are often found in
patients with liver cirrhosis and hepatoma.
Streptokinase
Streptokinase (SK) is an exogenous plasminogen
activator of 47 kDa, derived from streptococci
bacteria. It is not an enzyme and functions by
forming a stoichiometric 1:1 complex with human
plasminogen.This complex can function as an
activator of other plasminogen molecules. Complex
formation is accompanied by a conformational
change in the plasminogen molecule, exposing the
active site to activate a second plasminogen molecule
and is followed by the conversion of the SKplasminogen
into a SK-plasmin complex. Both types
of SK-complexes are equally efficient activators of
plasminogen (Figure 4).
SK + Pg [SK•Pg]
[SK•Pg] + Pg [SK•Pm] + Pm
[SK•Pm] + Pg [SK•Pm] + Pm
Figure 4. The sequence of streptokinase (SK), human plasminogen
(Pg) and plasmin (Pm) reactions. 8