Enzyme Inhibition by alpha-2 macroglobulin

Question

Alpha-2 macroglobulin is a plasma protein which acts as an anti-protease. It does so by a "bait mechanism" - the protease cleaves the bait domain, following which a conformational change causes binding of alpha2-macroglobulin with the protease, and consequent irreversible inhibition of the protease.

This seems to be very similar to "suicide inhibition" or "mechanism based inhibition" - when an enzyme catalyses a substrate analog's conversion to an active inhibitor, which subsequently binds strongly to the enzyme to inactivate it.

Is alpha2-macroglobulin's inhibition of proteases a case of suicide inhibition then? If it is, why is not more commonly described as that (I have not come across any description of alpha2-macroglobulin as a suicide inhibitor)?

Answer 1

Lets first see the proper definition of Suicide Inhibition as given by Wikipedia (emphasis mine):

In biochemistry, suicide inhibition, also known as suicide inactivation or mechanism-based inhibition, is an irreversible form of enzyme inhibition that occurs when an enzyme binds $\alpha$ substrate analogue and forms an irreversible complex with it through a covalent bond during the "normal" catalysis reaction. The inhibitor binds to the active site where it is modified by the enzyme to produce a reactive group that reacts irreversibly to form a stable inhibitor-enzyme complex. This usually uses a prosthetic group or a coenzyme, forming electrophilic alpha and beta unsaturated carbonyl compounds and imines.

Now, lets see how $\alpha$-2-Macroglobulin works, again by Wikipedia (emphasis mine):

$\alpha$M protease inhibitors inhibit by steric hindrance. The mechanism involves protease cleavage of the bait region, a segment of the $\alpha$M that is particularly susceptible to proteolytic cleavage, which initiates a conformational change such that the $\alpha$M collapses about the protease. In the resulting $\alpha$M-protease complex, the active site of the protease is sterically shielded, thus substantially decreasing access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain (RBD). RBD exposure allows the $\alpha$M protease complex to bind to clearance receptors and be removed from circulation.

So, clearly, it is not suicide inhibition as:

• $\alpha$M protease inhibitor does not form an irreversible complex with the protease, instead it uses steric hindrance to prevent protease from binding any substrate.
• this inhibition does not occur during the "normal" catalysis reaction, it is after the protease has catalyzed a reaction that the inhibitor covers it up, more like the consequence of catalysis.
• the inhibitor does not bind to protease active site, it covers the active site like a shield.

Putative mechanism of protease entrapment and inhibition by ECAM (Escherichia coli Alpha-2 Macroglobulin)

References:

1. Suicide Inhibition
2. $\alpha$-2 Macroglobulin
3. Structure of protease-cleaved Escherichia coli $\alpha$-2 macroglobulin reveals a putative mechanism of conformational activation for protease entrapment (PDF)