How Drugs Bind to their Targets 2 Flashcards
Describe the different steps involved in cholinergic neurotransmission.
- Synthesis of ACh
- Storage of ACh in vesicles
- Release of ACh
- Activation of mAChR or nAChR
- Degradation of ACh by AChE
- Recycling of Choline
What are the two cholinesterase subtypes?
Acetylcholinesterase
Butyrylcholinesterase
Describe the structure of the acetylcholinesterase enzyme.
- Membrane-bound and soluble forms
- Expressed in close proximity to ACh receptors
- Three branches with separate enzymes on each branch
- Enzymes consist of 4 subunits
Describe the two parts of the Active Site of Acetylcholinesterase.
Peripheral (or anionic) binding site
- Attracts acetylcholine into the site N-methyl group of acetylcholine forms π-cation bond
- transferred down the “gorge” into the active site by a series of π-cation interactions
Catalytic Site
- N-methyl group stabilised by a Tryptophan
- Serine, Histidine and Glutamate residues form the catalytic triad
Describes the steps in the hydrolysis of acetylcholine.
Step 1 = Acylation
- Acyl group attaches to cholinesterase with free Choline.
Step 2 = Deacylation
- Acylated enzyme detaches the acyl group from the enzyme to produce free acetic acid.
Compare the hydrolysis of acetylcholine with that of neostigmine.
Instead of acylation and deacylation, neostigmine hydrolysis is by carbamylation and decarbamylation.
Why are organophosphates more toxic than carbamates?
Organophosphates are irreversible and inhibit AChE, leading to poisoning since overproduction of ACh and build up in synapse.
How can AChE be reactivated after organophosphate poisoning?
AChE can be reactivated by phosphorylating the enzyme and adding a regeneration agent.
Name some conditions that can be treated with AChE inhibitors.
Myasthenia Gravis
Glaucoma
Alzheimer’s
Antidote for nerve gas poisoning
