fibrinolysis

Alpha2-macroglobulin is a large protein that is present in plasma. It is synthesized by liver cells and fibroblasts. It’s main functions are the inhibition of proteinases; for example it inhibits plasmin (thus inhibiting fibrinolysis) and thrombin (thus inhibiting coagulation). However, it technically has the ability to inhibit proteases from all catalytic classes, as well as the potential to have its inhibitory function removed (via reaction of it’s thiol ester group with any primary amine group).

The main mechanism by which it inhibits proteases is by steric hindrance: when the alpha2-macroglobulin approaches a protease, the protease cleaves the vulnerable region on the alpha2-macroglobulin (called a “bait” region) thus causing the alpha2-macroglobulin to collapse onto the protease. As a result of collapsing onto the protease, the alpha2-macroglobulin blocks the proteases active site.

I stumbled upon alpha2-macroglobulin after discovering that it irreversibly inhibits matrix metalloproteinases (MMPs). It does so by forming a complex with MMP which is then recognized by macrophages and removed by scavenger receptor-mediated endocytosis. It also inhibits various serine elastases.

Alpha2-macroglobulin binds to cytokines, and growth factors such as PDGF, bFGF, TGF-beta, and insulin. As a result, it may act as a carrier protein by delivering these messengers throughout the body.

Apparently, alpha2-macroglobulin is not implicated in diseases, although its plasma concentration can increase during nephrotic syndrome, and chronic renal failure can lead to chronically elevated alpha2-macroglobulin, which can result in an amyloid. In addition, a polymorphism of the alpha2-macroglobulin can increase risk for developing Alzheimer’s disease, but it’s also worth mentioning that in a transgenic mice experiment, serum alpha2-macroglobulin levels during Alzheimer’s progression were unchanged. So while the plasma levels don’t change during Alzheimer’s, an altered function of alpha2-macroglobulin due to a genetic polymorphism may explain the fact that it increases risk for developing Alzheimer’s.

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