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 a2–Plasmin
Inhibitor and Fibrinolysis. The
primary physiological inhibitor of plasmin is a2–plasmin
inhibitor. The binding
of a2
–plasmin inhibitor to plasmin(ogen) plays a
critical role in fibrinolysis. The binding
of circulating free plasmin(ogen) by a2
–plasmin inhibitor prevents both zymogen and
enzyme from
binding to fibrin and ultimately initiating
fibrinolysis. a2–Plasmin
inhibitor already crosslinked to fibrin
prevents plasmin catalytic action on local sites of
fibrin deposition as well as impeding subsequent
activation of plasminogen via plasminogen activator.
α2 –plasmin inhibitor
(α2 -PI) is a single-chain glycoprotein and is one of the major serine proteinase inhibitors circulating in plasma. Physiologically, it is the predominant inhibitor of
plasmin and it therefore plays a significant role in the specific inhibition of fibrinolysis. The role of
α2
-PI in fibrinolysis is three fold: covalent inhibition of plasmin; interference with the binding of
plasminogen to fibrin; and factor XIIIa catalyzed cross-linking of
α2-PI to fibrin (1). Rapid inactivation of plasmin proteolytic activity occurs through a two-step process. The inhibitor first forms a reversible complex with plasmin which is sub-sequently followed by the formation of a covalent, enzymatically inactive, complex with the catalytic site in plasmin (2,3).
α2-PI also functions by interfering with the binding of plasminogen to fibrin, effectively slowing the activation of plasminogen by fibrin-bound plasminogen activator (4). The interference in binding ultimately delays the initiation of fibrinolysis. Covalent cross-linking of a2-PI to the a-chains of fibrin which is mediated by factor XIIIa, protects crosslinked fibrin clots from plasmin degradation and thereby markedly stabilizes the fibrin clot against fibrinolysis (5). Failure to protect the fibrin clot from rapid dissolution before injured vessels can be restored results in a bleeding tendency described in patients with a deficiency in
α2-PI or
factor XIII (6,7).
The structure of α2-PI consists of three functionally important regions. A reactive site is located at
Arg-364 that forms a covalent bond with the plasmin active site (8). A high affinity plasminogen-binding site located within the last 20 COOH-terminal amino acids is responsible for binding the
NH2 -terminal kringle structures of plasmin(ogen) (4). An endogenous partially degraded form (non-plasminogen-binding form) of
α2-PI lacking this COOH-terminal region makes up about 30% of the circulating
α2-PI found in normal plasma (9). Lastly, the cross-linking site in
α2-PI is located in the
NH2 -terminal part of the molecule at Gln-2 (10).
α2–plasmin inhibitor is prepared from fresh frozen plasma by a combination of ion exchange,
affinity, and gel filtration chromatography steps. Our purification selects exclusively for the native
plasminogen-binding form. Purified
α2
–plasmin inhibitor is supplied in 50 mM potassium phosphate, 7.5 mM KCl, 0.075 mM EDTA, pH 7.4 and should be stored at -70°C. Purity is assessed by SDS-PAGE analysis and plasmin inhibition assay.
Properties of
α2 –plasmin inhibitor
|
Localization |
Plasma |
| Mode of action: |
Inhibits plasmin by forming an
irreversible complex with the catalytic active
site. Prevents the binding of plasmin to
fibrin. Cross-linked by factor XIIIa to fibrin. |
|
Plasma Concentration: |
69 µg/ml (1) |
| Molecular weight: |
58,700 single-chain (determined from amino
acid sequence and 14% carbohydrate) and 67,000
(determined by SDS-PAGE) (1) |
| Extinction coefficient: |
|
|
Isoelectric Point: |
Unknown
|
| Structure: |
Circulates as single chain molecule
consisting of 452 amino acids (1). |
| Percent carbohydrate: |
14% (w/w)
(1) |
|
Catalog
Number |
Description |
|
HA2AP-0230 |
α2 –Plasmin
Inhibitor |
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References
1. Aoki, N. et al., Methods Enzymol., 223, 185-197 (1993).
2. Moroi, M. and Aoki, N., J. Biol. Chem., 251, 5956 (1976).
3. Wiman, B. and Collen, D., J. Biol. Chem., 254, 9291 (1979).
4. Moroi, M. and Aoki, N., Thromb. Res., 10, 851 (1977).
5. Sakata, Y. and Aoki, N., J. Clin. Invest., 69, 536 (1982).
6. Aoki, N. et al., J. Clin. Invest., 63, 877 (1979).
7. Israels, E. D. et al., J. Clin. Invest., 52, 2398 (1973).
8. Holmes, W. E. et al., J. Biol. Chem., 262, 1659 (1987).
9. Kluft, C. and Los, N., Thromb. Res., 21, 65 (1981).
10. Tamaki, T. and Aoki, N., J. Biol. Chem., 257, 14767 (1982).
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