Acetylcholinesterase inhibitors
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Acetylcholinesterase inhibitors
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[post_date] => 2024-12-23 18:13:02
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[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Acetylcholinesterase (AChE) is a serine hydrolase whose primary function is to degrade acetylcholine (ACh) into acetate and choline molecules, terminating neurotransmission. AChE inhibitors, or anticholinesterases, inhibit cholinesterase enzymes from breaking down ACh. According to the mode of action, AChE inhibitors can be divided into two groups based on their mode of action: reversible and irreversible. Reversible inhibitors, which can be competitive or noncompetitive, have mostly therapeutic applications, whereas irreversible inhibitors are mostly associated with toxic effects.
Sarin is a gaseous organophosphate compound that acts as an irreversible AChE inhibitor. Because of its extreme toxicity, it is traditionally used in chemical warfare. Exposure to sarin can result in tremors, seizures, hypothermia, paralysis, and ultimately peripherally-mediated respiratory arrest. The standard treatment for sarin-like nerve agent exposure includes post-exposure injection of atropine – an ACh receptor antagonist – accompanied by an oxime. Oximes such as pralidoxime reactivate organophosphate-inhibited AChE by hydrolyzing the phosphorylated enzyme and separating the nerve agent phosphate from the AChE active site.
Mechanisms of inactivation of AChE by sarin and reactivation by pralidoxime are shown in Figure 1.
Figure 1 Mechanism of AChE inactivation (a) and reactivation (b)
Reversible acetylcholinesterase inhibitors are used to treat various neurological disorders, including Alzheimer's disease and myasthenia gravis (an autoimmune disease caused by auto-antibodies that inhibit muscarinic ACh receptors). Pyridostigmine is a competitive inhibitor of acetylcholinesterase that helps relieve symptoms experienced by myasthenia gravis patients.
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[question] => Where does acetylcholine NOT function as the primary neurotransmitter?
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[answer] => 3
[description] => Reason for Correct Answer:
Acetylcholine (ACh) is a neurotransmitter that is released from pre-synaptic neurons to bind to acetylcholine receptors on post-synaptic neurons or muscle cells.
ACh binds to nicotinic acetylcholine receptors (nAChRs) within the central nervous system and within the neuromuscular junction (Choice D). ACh binds to muscarinic receptors in both the central and peripheral nervous systems. In the autonomic nervous system, ACh functions as a key neurotransmitter in both the parasympathetic and sympathetic divisions.
In the parasympathetic nervous system, ACh is the main neurotransmitter released by both the preganglionic (Choice A) and postganglionic (Choice C) neurons.
In the sympathetic nervous system, ACh is the main neurotransmitter released by preganglionic neurons only; norepinephrine (NE) is the main neurotransmitter released by postganglionic sympathetic neurons. A summary of this is shown below.
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[each_answer] => A. Preganglionic parasympathetic neurons
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[1] => Array
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[each_answer] => B. Postganglionic parasympathetic neurons
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[each_answer] => C. Postganglionic sympathetic neurons
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[3] => Array
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[each_answer] => D. Neuromuscular junctions
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => How would you expect pyridostigmine to affect the apparent Km and Vmax values of the acetylcholinesterase enzyme?
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[answer] => 1
[description] => Reason for Correct Answer:
The passage states that pyridostigmine is a competitive inhibitor of acetylcholinesterase.
The Km value is a measure of the affinity of the enzyme for its substrate; it is equal to the substrate concentration needed to reach ½ of the maximum velocity. (So, higher Km means lower substrate affinity.)
The Vmax value is used to measure the maximum velocity of an enzymatic reaction, which is reached at very high substrate concentrations
Competitive inhibitors compete with the substrate for binding to the enzyme, thus effectively decreasing binding affinity between the enzyme and the substrate and increasing Km. However, with increased substrate concentration, the substrate can effectively outcompete the inhibitor; therefore, the Vmax of the reaction is not changed.
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[each_answer] => A. Km would increase and Vmax would remain unchanged.
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[each_answer] => B. Km would decrease and Vmax would remain unchanged.
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[each_answer] => C. Km and Vmax would both increase.
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[each_answer] => D. Km and Vmax would both decrease.
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[quiz_unique_key] => 1403770772
[question] => Enzyme X is activated by the presence of acetate ions, whereas enzyme Y is deactivated by downstream effector molecules that are synthesized following acetylcholine receptor activation.
How would you expect the presence of sarin to affect the rate of an enzyme X or enzyme Y-catalyzed reaction?
[value] => Array
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[description] => Reason for Correct Answer:
The presence of an enzyme increases the rate of a chemical reaction. The more active enzyme present, the faster the rate of the reaction will be.
For this problem, we are dealing with two enzymes, X and Y, that are activated by the presence of acetate ions and inactivated by the acetylcholine receptor activation, respectively. If we relate this to the acetylcholinesterase catalyzed conversion of acetylcholine to acetate and choline, it will look something like this:
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[answers] => Array
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[each_answer] => A. Sarin would increase the rate of the enzyme X-catalyzed reaction by decreasing the amount of available acetate.
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[1] => Array
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[each_answer] => B. Sarin would increase the rate of the enzyme X-catalyzed reaction by increasing the amount of available acetate.
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[each_answer] => C. Sarin exposure would decrease the rate of the enzyme Y-catalyzed reaction by increasing the level of acetylcholine receptor activation.
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[each_answer] => D. Sarin exposure would decrease the rate of the enzyme Y-catalyzed reaction by decreasing the level of acetylcholine receptor activation.
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[quiz_unique_key] => 1403770772
[question] => Which molecules would pyridostigmine bind during its inhibition of acetylcholinesterase?
I. Free Enzyme
II. Enzyme-substrate complex
III. Free Substrate
[value] => Array
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[answer] => 1
[description] => Reason for Correct Answer:
The passage states that pyridostigmine is a competitive inhibitor of acetylcholinesterase.
Unlike competitive inhibitors, noncompetitive (allosteric) inhibitors bind to the free enzyme OR enzyme-substrate complex, and uncompetitive inhibitors bind to the enzyme-substrate complex only.
Competitive inhibitors can bind to enzymes only when they are not bound to substrate, because both the inhibitor and the substrate compete for the same binding site. As such, competitive inhibitors will bind to free the enzyme, but not to the enzyme-substrate complex or free substrate.
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[0] => Array
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[each_answer] => A. I only
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[1] => Array
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[each_answer] => B. II only
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[each_answer] => C. I & II
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[each_answer] => D. I, II, & III
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[question] => Reversal of organophosphate toxicity is complicated by a phenomenon known as aging, a reaction in which the enzyme-bound organophosphate molecule loses the alkyl (–R) group of its alkoxy (–OR) substituent; this results in a negative charge on the enzyme-bound organophosphate and further strengthens its bonds to AChE.
Given this information, which medication would be most appropriate for an individual who has already been exposed to sarin for a significant amount of time prior to receiving treatment?
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[answer] => 3
[description] => Reason for Correct Answer:
The new information given in the question stem says that the covalent bond between AChE and organophosphates like sarin may increase over time (a process called aging).
This would make it harder for oximes like pralidoxime to reverse the inhibition of AChE by organophosphates like sarin. (The passage states that these oximes act to separate sarin from AChE and, in fact, Figure 1 shows that pralidoxime’s mechanism involves breaking the covalent bond between sarin and AChE, so this would be harder after aging.)
According to the passage, atropine is an ACh receptor antagonist, which means that it will counteract the effect of the ACh surge directly, which is especially helpful in the case where AChE cannot be easily reactivated.
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[each_answer] => A. Pralidoxime, because it can remove sarin from the AChE enzyme without breaking a covalent bond.
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[each_answer] => B. Pralidoxime, because it would remove sarin from affected cells.
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[each_answer] => C. Atropine, because it would counteract the effects of the irremediable acetylcholine surge.
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[each_answer] => D. Atropine, because it would reactivate inactive acetylcholinesterase enzymes.
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[quiz_unique_key] => 1325138223
[question] => What happens when ACh binds the motor endplate of a muscle cell?
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[answer] => 4
[description] => Reason for Correct Answer:
When ACh binds to the motor endplate of a muscle cell, it interacts with ligand-gated ion channels called nicotinic receptors. These receptors are specific to ACh and are located on the muscle cell membrane at the motor end plate.
When ACh binds to these receptors, it causes them to open, allowing sodium ions (Na+) to flow into the muscle cell. This influx of Na+ ions leads to depolarization of the muscle cell membrane, initiating an action potential and ultimately triggering muscle contraction. This action potential propagates across the muscle cell, leading to the release of calcium ions (Ca2+) from the sarcoplasmic reticulum. The calcium ions then participate in the process of muscle contraction by enabling actin and myosin filaments to interact and generate force.
Because binding of ACh to receptors causes them to open, allowing Na+ to enter, they are considered ligand-gated ion channels. See schematic of signal transmission at the neuromuscular junction below.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Voltage-gated ion channels allow Ca2+ influx into the cell.
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[each_answer] => B. Voltage-gated ion channels allow Na+ influx into the cell.
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[each_answer] => C. Ligand-gated ion channels allow Ca2+ influx into the cell.
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[each_answer] => D. Ligand-gated ion channels allow Na+ influx into the cell.
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Figure 1
