Acetylcholinesterase catalysis and inhibition
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Acetylcholinesterase catalysis and inhibition
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[ID] => 560304
[post_author] => 12815
[post_date] => 2025-01-14 06:56:30
[post_date_gmt] => 2025-01-14 11:56:30
[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 key enzyme in both central and peripheral cholinergic neurotransmission. AChE catalyzes the hydrolysis of acetylcholine (ACh) with high efficiency. Its catalytic site (a triad of important residues) is located inside a deep cavity, or gorge. The active-site is represented by Figure 1.
Figure 1. Catalytic active-site model of acetylcholine
ACh has been identified in a number of non-neuronal tissues in animals, fungi, bacteria, and even in plants, which lack a nervous system entirely. ACh-hydrolyzing activity in plant tissue is inhibited by neostigmine bromide, which is a known inhibitor of the animal AChE.
To compare plant and animal enzymes, scientists studied the activity of AChE taken from maize and electric eel. In vitro assays were used to measure the hydrolysis of thiocholinesters containing acyl chains of different lengths – namely acetylthiocholine (ASCh) an propionylthiocholine (PpSCh). Kinetic data are shown in Table 1.
Table 1. Kinetic data of the plant and animal AChE; Km is expressed in mM and Vmax in μmol min−1 mg−1
To examine the inhibitory effects of neostigmine bromide on the hydrolyzing activities of AChE, both plant and animal enzymes were pre-incubated with neostigmine bromide followed by addition of substrates (6mM or 12mM) to the reaction. Dixon plots showing the reciprocal of the reaction rate against the inhibitor concentration ([I] on x-axis) are shown in Figure 2.
Figure 2. Inhibitory efficiency of neostigmine bromide on maize and eel AChE
In Dixon plots, the lines for different substrate concentrations intersect. For competitive inhibition, the lines typically intersect above the x-axis, whereas for non-competitive inhibition, the lines intersect on the x-axis. The inhibitor constant Ki represents the concentration of the inhibitor required to produce half maximum inhibition or the concentration at which the inhibitor occupies 50% of the receptor sites.
Adapted from Ramsay RR, Tipton KF. Assessment of enzyme inhibition, 2017; and Sagane Y et al. Molecular characterization of maize acetylcholinesterase, 2005.
[post_title] => Acetylcholinesterase catalysis and inhibition
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[post_name] => acetylcholinesterase-catalysis-and-inhibition
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[post_modified] => 2025-05-04 07:50:44
[post_modified_gmt] => 2025-05-04 11:50:44
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[question] => The AChE catalytic triad is made up of which of the following residues?
[value] => Array
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[answer] => 1
[description] => Reason for the Correct Answer:
Figure 1 shows interactions between side chains (R-groups) of the residues (amino acids) making up the catalytic triad.
The residue on the left has a hydroxyl group, which means it could be serine (R group = -CH2OH) or another -OH containing residue.
The residue must be histidine, which contains an imidazole ring.
The residue on the right has a carboxylic acid, which means that it could be aspartic acid (asp) or glutamic acid (glu). Note that it is clear that the entire R group is not shown in the figure.
Here is a summary of amino acids:
https://commons.wikimedia.org/wiki/File:ProteinogenicAminoAcids.svg
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[answers] => Array
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[0] => Array
(
[each_answer] => A.Ser-His-Glu
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[1] => Array
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[each_answer] => B.Thr-Leu-Val
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[2] => Array
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[each_answer] => C.Thr-Lys-Phr
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[3] => Array
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[each_answer] => D.Ser-Lys-Trp
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[1] => Array
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[quiz_unique_key] => 3873426850
[question] => AChE does not cleave esters with bulkier acyl groups. What is the likely reason for this?
[value] => Array
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[answer] => 3
[description] => Reason for the Correct Answer:
The passage demonstrates that AChE is able to cleave a variety of thiocholinesters, so there is no reason to conclude that it lacks a mechanism for catalyzing larger ones.
However, Figure 1 shows that the location of its catalytic site is within a deep cavity, or gorge.
It is most reasonable to conclude that steric hindrance prevents esters with large acyl groups from entering and reaching the active site.
Note that the passage shows that the enzyme can cleave small esters that are larger than acetylcholine, as evidenced by enzymatic activity with propionylthiocholine (PpSCh), so there is no reason to conclude that the active site doesn’t accommodate esters any larger than acetylcholine (as in Choice B). This option is too extreme.
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[0] => Array
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[each_answer] => A.The bulkier acyl groups interfere with essential catalytic residues within the active site, preventing catalysis.
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[1] => Array
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[each_answer] => B.The shape of the active site is optimized for small substrates no larger than acetylcholine.
)
[2] => Array
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[each_answer] => C.Esters with large acyl groups are hindered sterically from reaching the active site for catalysis.
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[3] => Array
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[each_answer] => D.AChE lacks a mechanism for cleaving esters with bulkier acyl groups.
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[2] => Array
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[quiz_unique_key] => 2377279144
[question] => The graph below compares substrate selectivity of plant and animal AChE for another substrate, S-butyrylthiocholine (BSCh), to substrate selectivity data for ASCh and PpSCh. What can be interpreted from the data?
[value] => Array
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[answer] => 1
[description] => Reason for the Correct Answer:
The structures of each compound are shown above their data. You have to determine which data corresponds to acetylthiocholine (ASCh), propionyl thiocholine (PpSCh), and S-butyrylthiocholine (BSCh). Notice that the structures differ in what’s shown to the right of the sulfur atom.
You should be familiar with the basic difference between sizes of things that have acetyl, propionyl, and butyryl components, like those shown here.
We can tell then that the order of the data shown is ASCh, then PSCh, then BSCh.
The graph shows that there was the greatest reactivity and therefore substrate specificity of the maize AChE for PpSCh (middle data), then ASCh (left data), then BSCh (right data).
)
[answers] => Array
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[0] => Array
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[each_answer] => A.Substrate selectivity of the maize AChE was estimated as PpSCh > ASCh ≫ BSCh.
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[1] => Array
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[each_answer] => B.BSCh is an ideal substrate for both AChEs.
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[2] => Array
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[each_answer] => C.Substrate selectivity of the maize AChE was estimated as ASCh > PpSCh ≫ BSCh.
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[3] => Array
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[each_answer] => D.Substrate selectivity of animal AChE was estimated as BSCh > PpSCh ≫ ASCh.
)
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[quiz_unique_key] => 1723550837
[question] => Which of the following statements is consistent with the data presented in Figure 2?
I. Neostigmine bromide inhibited the hydrolytic activity of the purified maize AChE in a competitive manner.
II. The inhibitory reagent binds to the catalytic site of the animal AChE.
III. Maize AChE likely has an active site similar to that of the animal AChE.
[value] => Array
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[answer] => 4
[description] => Reason for the Correct Answer:
The last paragraph explains how to interpret a Dixon plot to identify types of inhibitors: “…the lines for different substrate concentrations intersect. For competitive inhibition, the lines typically intersect above the x-axis, whereas for non-competitive inhibition, the lines intersect on the x-axis.”
The graphs shown show the lines intercepting above the x-axis, suggesting that this is competitive inhibition, for both the maize and eel AChE. (Option I is correct.)
Competitive inhibitors bind to the active site. (Option II is correct.)
The data are also consistent with the notion that maize and animal AChE have similar active sites, since they bind the same inhibitor. (Option III is correct.)
)
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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.I and II only
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[2] => Array
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[each_answer] => C.II and III only
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[3] => Array
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[each_answer] => D.I, II, and III
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[4] => Array
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[quiz_unique_key] => 2261298308
[question] => What is true about the reaction catalyzed by AChE, where ACh is the substrate?
[value] => Array
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[answer] => 2
[description] => Reason for the Correct Answer:
The passage states that acetylcholinesterase (AChE) catalyzes a hydrolysis reaction to break down acetylcholine (as well other cholinesters as shown by the research presented).
Acetylcholine is broken down into choline and acetate, or acetic acid, which are therefore products of the reaction.
Hydrolysis reactions consume water to break down other compounds, as shown here:
)
[answers] => Array
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[0] => Array
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[each_answer] => A.Water is produced by the reaction, and choline is produced.
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[each_answer] => B.Water is consumed by the reaction, and acetate is produced.
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[2] => Array
(
[each_answer] => C.Hydrogen peroxide is produced by the reaction, and acetate is consumed.
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[each_answer] => D.Hydrogen peroxide is consumed by the reaction, and choline is consumed.
)
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[quiz_unique_key] => 83407773
[question] => Which statement is supported by the data presented in the passage?
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[answer] => 3
[description] => Reason for the Correct Answer:
The Km and Ki values in the passage will give you an estimate of the affinity of the enzyme for the substrates and inhibitor, respectively.
Km is equal to half of the substrate concentration at ½ Vmax; a larger Km indicates a smaller affinity for the substrate.
The Km values in Table 1 indicate that the plant enzyme (higher Km) has lower affinity for the substrate; this also means the plant enzyme is saturated more slowly with substrate.
The passage states that “The inhibitor constant Ki represents the concentration of the inhibitor required to produce half maximum inhibition or the concentration at which the inhibitor occupies 50% of the receptor sites.” It is therefore a measure of the enzyme for the inhibitor.
The data show that the plant enzymes have a higher Ki than the animal enzymes. This means that they require more inhibitor to reach ½ maximum inhibition, and that they have lower affinity for the inhibitor (neostigmine bromide).
)
[answers] => Array
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[0] => Array
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[each_answer] => A.The plant enzyme requires a lower concentration of neostigmine bromine to reach the same level of inhibition, compared to the animal enzyme.
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[each_answer] => B.The plant enzyme has high affinity for thiocholinester substrates compared to the animal enzyme.
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[2] => Array
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[each_answer] => C.The plant AChE exhibits lower affinity for neostigmine bromide compared to the animal enzyme.
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[each_answer] => D.The plant enzyme is saturated with substrate faster than the animal enzyme.
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[560304|1] => A
[560304|2] => C
[560304|3] => A
[560304|4] => D
[560304|5] => B
[560304|6] => C
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