Lipitor Mechanism of Action (TSA)

[weanprednisone]

TSA mimics TS to inhibit S from binding to E.

How is Lipitor (aka. HMG-CoA reductase TSA) lowering cholesterol?

With my very basic knowledge, is Lipitor basically binding to the enzyme, blocking the substrate that increases cholesterol, therefore loweirng cholesterol overall? I'm guessing its way more complicated than this.

Also I've read in a biochem textbook that TSA permentally binds to the enzyme, forever preventing S to bind. Does this initiate somesort of feedback to make more enzymes in order to try to bind to substrates? Is this the reason why Lipitor is not a one-time thing medication-meaning you have to continuously take it?

Probably won't be on the MCAT, but very interested in knowing!

Thanks in advance!

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[aldol16]

Lipitor actually is not an irreversible inhibitor. Lipitor is a competitive inhibitor of, as you say, HMG-CoA reductase. This is the committed step in cholesterol biosynthesis via the mevalonate pathway (basically linking up isoprene units to make squalene, which can be cyclized into cholesterol and further derivatized with monooxygenases, etc. Therefore, Lipitor basically stops your body from making cholesterol.

Since it's a competitive inhibitor, it binds to the enzyme active site so that the actual substrate (HMG-CoA) cannot be reduced. Competitive inhibition also implies that enzyme activity can still be recovered if HMG-CoA concentration were elevated to saturation levels.

 

[weanprednisone]

Thank you @aldol16
So we can say that TSA is under the umbrella of competitive inhibitors?
Competitive inhibitors are never permanently bound to enzymes, unless the AS residues have covalent interactions with the inhibitor? Therefore the reason why pts have to continuously take Lipitor is because the protein sequences w/in Lipitor can be degraded in the Liver and do not have any covalent interactions with the residues, meaning HMG-CoA will be available for HMG-CoA reductase again->eventually synthesizing cholesterol.

 

[aldol16]

So we can say that TSA is under the umbrella of competitive inhibitors?

I believe so. If an inhibitor is acting as a transition-state analog, that means it has to bind to the active site and if it binds to the active site reversibly, it's a competitive inhibitor.

Competitive inhibitors are never permanently bound to enzymes, unless the AS residues have covalent interactions with the inhibitor? Therefore the reason why pts have to continuously take Lipitor is because the protein sequences w/in Lipitor can be degraded in the Liver and do not have any covalent interactions with the residues, meaning HMG-CoA will be available for HMG-CoA reductase again->eventually synthesizing cholesterol.

I don't know the pharmacology of Lipitor but you could probably find the pharmacokinetic data via a simple Google search. That will tell you the rate of P450 metabolism. But yes, competitive inhibitors are never permanently bound to enzymes because competitive inhibitors, by definition, bind reversibly. That's why you can always knock the inhibitor off the enzyme by using more substrate.