Terms in this set (41)
How does AChE inactivate ACh?
Describe the interactions between ACh and AChE.
In the "anionic subsite" of the enzyme, the positively charged quat. N of ACh forms a cation-pi bond with the phenyl ring of a tryptophan residue on the enzyme. The ester of ACh forms 3 H-bonds with residues on the enzyme in the "oxyanion hole."
What anchors the ACh molecule to the active site of AChE?
The quaternary ammonium.
What is the "catalytic triad"?
The neutrophilic O of glutamine attacks the H on the N of the ring in histidine, which then attacks the H of the hydroxyl group of serine. The neutrophilic O of serine can then attack the C of the ester in ACh that is docked in the active site, kicking off a molecule of choline and acetlyating the enzyme. (See handout for diagram)
What happens after ACh is hydrolyzed into choline and the acetylated enzyme?
Choline dissociates away and the acetyl group is rapidly hydrolyzed off of the enzyme, regenerating the OH group of the serine residue on the enzyme.
What is the final result of the deactivation of ACh by AChE?
A molecule of acetic acid, a molecule of choline, and a regenerated enzyme with a free OH group to perform another hydrolysis.
Does the hydrolysis of ACh by AChE happen slowly or quickly?
Very quickly (microseconds).
What are the 3 types of AChEIs?
Competitive inhibitors, reversible inhibitors, and irreversible inhibitors.
How do competitive AChEIs work?
They have greater affinity for AChE than ACh does, but they have no intrinsic activity (i.e. doesn't react, just takes up space).
Competitive AChEI that binds to the anionic subsite of the enzyme. Used in diagnosing myasthenia gravis.
Why is edrophonium useful in diagnosing MG?
If the drug is administered and muscle strength rapidly returns to normal, the patient likely has MG.
How do competitive AChEIs, like edrophonium, have to be administered?
Has to be injected due to the quat. N (charged group=cannot pass through membranes).
What is the general time of onset and duration of action of a competitive AChEI?
Rapid acting and short duration of action.
How do reversible AChEIs work?
React with AChE to form a carbamylated enzyme, which is more stable than an acetylated enzyme, but still capable of being hydrolyzed and regenerated.
What is a carbamate?
Part ester, part amide.
Reversible AChEI that carbamylates AChE.
What is the most basic N of physostigmine and what is it's significance?
N furthest away from the phenyl ring (on the right in this diagram). It's electrons are not shared (most available). pKa of about 8. Part that binds to anionic subsite.
How long does it take for AChE to regenerate its active site after being carbamylated with physotigmine (i.e. what is the half life of physostigmine)?
About 15 minutes.
Why does it take longer to hydrolyze a carbamylated enzyme than an acetylated enzyme?
The N of the carbamate causes resonance and makes the C of the carbonyl less electrophilic and more stable to hydrolysis than an ester (i.e. the C of the carbonyl is a worse electrophile and is not as likely to be attacked by a nucleophile).
What is the half life of neostigmine?
What is the half life of pyridostigmine?
Why are the half lives of neostigmine and pyridostigmine longer than that of physostigmine?
The second methyl group on the N of the carbamate pumps more electron density toward the carbonyl making the C of the carbonyl less electrophilic and therefore more difficult to attack with a nucleophile.
Is physostigmine influenced by changes in pH? How does this affect its properties in the body?
Physostigmine has a tertiary amine that is influenced by pH changes. At a low pH, the amine will be extensively protonated (active). At a high pH, the amine will be non-ionized (inactive). At physiological pH, the majority of the molecules will be protonated (active), but some will not be. This means that a small portion of this drug will get into the brain at physiological pH.
Are neostigmine and pyridostigmine influenced by changes in pH? How does this affect its properties in the body?
Neostigmine and pyridostigmine have a quaternary amine that will always be charged no matter the pH. This means that the drug will never pass through the BBB.
How can an AChEI be used to treat Alzheimer's?
There is a loss of cholinergic neurons in Alzheimer's, so ACh needs to be increased. ACh can be increased in the synapse by inhibiting AChE.
AChEI that forms cation-pi bonds between the phenyl rings and tryptophan residues on the enzyme, and an ionic bond between the charged N and an aspartic acid residue on the enzyme. Blocks the active site reversibly.
AChEI that carbamylates the active site. Has more lipophilic groups to give it a longer half life of about 10 hrs.
Naturally occurring AChEI that has high CNS penetration. Also binds allosterically to nicotinic receptors to enhance the effect of ACh at these receptors.
What are irreversible AChEIs?
Inhibitors that don't allow regeneration of the active site of the enzyme.
What is the most common type of irreversible AChEI?
Irreversible organophosphorus AChEI used to treat glaucoma. Phosphorylates the active site of the enzyme- hydrolysis does not occur.
How long does it take to generate new AChE?
What are 5 common nerve gasses and how do they work?
Tabun, sarin, GF, soman, and VX. They are uncharged organophosphates that easily penetrate the BBB and bind irreversibly to AChE.
What is an oxime?
AChE reactivator used as an antidote for irreversible AChEIs.
When can antidotal therapy be used?
Antidotal therapy can only be used before the organophosphate has aged. This means the antidote must be given soon after exposure to the organophosphate.
Why does antidotal therapy not work on an aged phosphorylated enzyme?
O of water attacks the P to kick off one of the OR groups and replace it with an O- group in an aged phosphorylated enzyme. This O- makes the P much less electrophilic; therefore, the oxime is not able to react with it sufficiently. The negative charge would also repel the antidotal molecule that needs to bind to the anionic subsite.
Used as an antidote to organophosphate poisoning. O of hydroxyl group in oxime attacks P in phosphorylated enzyme to hydrolize the phosphate group.
What is selective toxicity in regards to insecticides?
Insecticides are metabolized in different ways/into different compounds in insects and in humans. These compounds become potent AChEIs in insects and are hydrolyzed into harmless substances in humans.
Insecticide that is a potent inhibitor of AChE in insects and is hydrolized in humans.
Insecticide that is a potent inhibitor of AChE in insects, but is hydrolized in humans.
What gives malathion and parathion their selectivity?
The P is double bonded to S instead of O, which makes P much less electrophilic; therefore, the P will not be attacked by the nucleophilic O of the serine residue on AChE. In insects, the S is substituted for O, causing it to react with AChE.
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