Friday, December 7, 2012

Mechanism of action of anticholinesterase enzyme

We are going to cover an exhausting topic today
Let's get started!

What is acetyl choline esterase?
It is an enzyme which catalyzes the hydrolysis of acetyl choline to acetate and choline

The active region of acetylcholine esterase contains an aromatic anionic site [near tryptophan 86] and an esteratic site formed by serine 203, glutamate 334 and histidine 447

Mnemonic:
aromaTic has T, so does Tryptophan
eSteratic site has S, so does Serine
[That's how I remember :D ]

I know it's a very complex molecule
Stay with me on this one.. It gets better when you visualize it
This is how I imagine it to look like ^_^


Acetyl choline esterase



How does acetyl choline react with acetyl choline esterase?
Hydrolysis of acetyl choline involves electrostatic attraction between the positive N+ of acetyl choline to the aromatic pocket and nucleophilic attack of serine-OH leading to acetylation of serine

Acetyl choline & acetyl choline esterase

Updated on 20th Oct, 2016 -  Image correction: It is acetylcholine* and not acetylcholine enzyme. 

Acetyl choline & acetyl choline esterase
The acetylated enzyme reacts with water to produce acetic acid and choline :)


How do Organophoshates react with acetyl choline esterase?
Organophosphates attach to the esteratic site
The anionic site is free

Organophoshates & acetyl choline esterase


If the organophosphate molecule loses it's alkyl group, it becomes resistant to hydrolysis
This process is called aging

So if you have to rescue your acetyl choline enzyme from the evil force of Organophosphorous compounds, you'll have to do it before aging (6-8 hours) :P
How do you do it? Use cholinesterase reactivators!

What are choline esterase reactivators?
They are used to restore neuromuscular transmission in cases of Organophosphate poisoning
You basically give more reactive OH groups.. Since the phosphorylated enzyme reacts very slowly or not at all with water
In the presence of Oximes, [Generic formula R-CH=N-OH], reactivation occurs much faster

Example of an Oxime is Pralidoxime
Let's see how they work!

Pralidoxime, organophosphate and acetyl choline esterase
Pralidoxime has a quarternary nitrogen which attaches to the anionic site
It's oxime end reacts with the phosphorous atom attached to the esteratic site
The oximephosphonate so formed diffuses away leaving the reactivated cholinesetrase :)

 That's all for today ^_^
*phew* That was a lot!
Lemme know if I have made any mistakes in the explanation or in the diagram, I'll correct it.

Have an awesome day!

-IkaN
Related post: Treatment of organophosphorus poisoning mnemonic

8 comments:

  1. Thanks...its a very great explaination...
    :)

    ReplyDelete
    Replies
    1. You're welcome. I remember writing this in second year, unsure of myself :)

      Delete
  2. thx alot... great and simple explanation

    ReplyDelete
  3. thanks that was really good :)

    ReplyDelete

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