Phenylalanine hydroxylase and phenylketonuria
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- Phenylalanine hydroxylase and phenylketonuria
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Phenylalanine hydroxylase and phenylketonuria
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[post_date] => 2024-12-23 06:32:16
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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.
Phenylalanine hydroxylase (PAH) is the rate-limiting enzyme of the phenylalanine metabolic pathway. Phenylalanine hydroxylase catalyzes the hydroxylation of the aromatic ring of phenylalanine, converting it to tyrosine, as shown in Figure 1. The PAH enzyme requires two cofactors - tetrahydrobiopterin (BH₄) and iron - to function.
Figure 1 Phenylalanine is converted to tyrosine by phenylalanine hydroxylase. Attribution: Phenylalanine hydroxylase, Overallreaction, Wikipedia.
Phenylketonuria (PKU) is an autosomal recessive genetic disorder that results from an inactivating mutation in the gene coding for PAH - the most common of which replaces cytosine (C) with adenine (A) at position 742 in the gene sequence. An alternate form of PKU results from a deficiency in the cofactor tetrahydrobiopterin. Those with PKU are unable to metabolize phenylalanine and convert it to tyrosine, resulting in a build-up of phenylalanine. Excess phenylalanine is then metabolized to form phenylpyruvate via the action of the enzyme phenylalanine transaminase. Without enzymes to remove phenylalanine, this amino acid can build up to dangerous levels, especially when food is consumed that is high in protein, such as meat, milk, nuts, and cheese.
Left untreated, PKU can lead to serious medical problems, including brain damage, behavior problems, and seizures. Treatments include a low-protein diet supplemented with a formula containing amino acids and other essential nutrients. There have been over 300 identified mutants that result in PKU, most of which are in the phenylalanine hydroxylase catalytic domain.
[post_title] => Phenylalanine hydroxylase and phenylketonuria
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[question] => How would you expect the mutation associated with PKU to affect the catalytic efficiency of phenylalanine transaminase?
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[answer] => 4
[description] => Reason for Correct Answer:
Kₘ is a measure of the affinity of the enzyme for the substrate, or the likelihood of binding.
Kₘ is calculated by the following formula. Notice how the k꜀ₐₜ is the rate constant of the enzymatic conversion (substrate to product); it is the “turnover number,” or the number of molecules that can be produced per second per active site of an enzyme.
Catalytic Efficiency is calculated by dividing k꜀ₐₜ by Kₘ.
Kₘ and k꜀ₐₜ measure kinetic parameters intrinsic to the enzymes and are independent of the substrate concentration. Thus, catalytic efficiency is also independent of substrate concentration.
In PKU, mutations affect the PAH enzyme; there is no mutation to phenylalanine transaminase and the phenylalanine transaminase reaction is only influenced by an increase in phenylalanine (substrate) concentration due to inability of PAH to break it down.
This increase in substrate concentration does not affect the intrinsic parameters of phenylalanine transaminase – namely k꜀ₐₜ Kₘ , and catalytic efficiency.
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[answers] => Array
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[each_answer] => A. k꜀ₐₜ will decrease, and Kₘ will increase, leading to a decreased catalytic efficiency.
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[each_answer] => B. k꜀ₐₜ will increase, and Kₘ will decrease, leading to an increased catalytic efficiency.
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[each_answer] => C. Neither K꜀ₐₜ nor Kₘ will change, leading to an unchanged catalytic efficiency.
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[each_answer] => D. More NTKA would enter the synapse, resulting in increased binding of postsynaptic receptors and more excitation.
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[1] => Array
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[quiz_unique_key] => 3243476205
[question] => Which likely describes the most common mutation in individuals with PKU?
I. Point mutation
II. Nonsense mutation
III. Missense mutation
IV. Silent mutation
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[answer] => 3
[description] => Reason for Correct Answer:
The passage states that the most common mutation in PKU “replaces cytosine (C) with adenine (A) at position 742 in the gene sequence”
This by definition, is a point mutuation. A point mutation occurs in a genome when a single base pair is added, deleted or changed. While most point mutations are benign, they can also have various functional consequences, including changes in gene expression or alterations in encoded proteins.
In this case, we know that the point mutation has an effect on the PAH enzyme.
Therefore, it cannot be a silent mutation (which has no effect) and must be a missense mutation – substitution of one amino acid for another – given the remaining answer choices.
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[0] => Array
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[each_answer] => A. I only
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[each_answer] => B. II only
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[each_answer] => C. I and III only
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[each_answer] => D. I and IV only
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[2] => Array
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[quiz_unique_key] => 2187790141
[question] => Given a deficiency in tetrahydrobiopterin, how might one go about calculating the kinetics of phenylalanine hydroxylase using the Michaelis-Menten equation?
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[answer] => 4
[description] => Reason for Correct Answer:
Examine the role of tetrahydrobiopterin in this reaction.
The presence of a cofactor means that it is possible for the enzyme to exist in forms aside from “E” and “ES.”
Michaelis-Menten kinetics are based on this reaction and use equations like this:
The presence of a cofactor violates one of the assumptions made during the derivation of the Michaelis-Menten equation, thereby giving the reaction non-Michaelis-Menten kinetics.
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[each_answer] => A. No modifications would be needed as there is no term in the Michaelis-Menten equation corresponding to cofactor concentration.
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[each_answer] => B. Since cofactors are also substrates, the term representing substrate concentration could be used to account for cofactor concentration.
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[each_answer] => C. The effects of the substrate would be incorporated into the k꜀ₐₜ value.
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[each_answer] => D. This reaction would exhibit non-Michaelis-Menten kinetics, so the Michaelis-Menten equation could not be used in this case as it stands.
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[quiz_unique_key] => 1579828684
[question] => How would you expect the mutation associated with PKU to affect the rate of the reaction catalyzed by phenylalanine transaminase?
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[answer] => 2
[description] => Reason for Correct Answer:
PKU involves mutations in phenylalanine hydroxylase (PAH), not phenylalanine transaminase.
PKU results in a buildup in phenylalanine, the substrate for phenylalanine transaminase.
The rate of an enzyme catalyzed reaction increases with substrate concentration. Therefore, the rate of the reaction will increase.
The maximum velocity, or Vₘₐₓ, of the reaction is the maximum achievable velocity as you raise the substrate concentration.
Since the Vₘₐₓ is a measure of enzyme function, it is not affected by substrate concentration, and the answer is Choice B.
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[each_answer] => A. The reaction rate will increase in proportion to an increase in the maximum velocity of the reaction, due to an increase in the concentration of phenylalanine.
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[each_answer] => B. The reaction rate and will increase, due to an increase in the concentration of phenylalanine, but the maximum velocity of the reaction will not change.
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[each_answer] => C. The reaction rate and maximum velocity of reaction will decrease, due to an increase in the concentration of phenylalanine.
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[each_answer] => D. The reaction rate will remain unchanged, as Km and Vmax have not changed.
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[question] => Individuals heterozygous for the PKU mutation have very slightly increased levels of phenylalanine. How would you expect the phenylalanine hydroxylase reaction rate of an individual heterozygous for the PKU mutation to be different from that of an individual with no mutated genes?
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[answer] => 1
[description] => Reason for Correct Answer:
Having a heterozygous PKU mutation would mean that a portion of the expressed phenylalanine hydroxylase will be mutated.
The passage suggests that the mutation results in no PAH function. A heterozygous individual would essentially lose the PAH made from one gene but still have functional PAH (with no affinity changes) from the other gene. So, this would effectively be a reduced enzyme concentration – or a lower effective [E]T value.
A reaction’s Vₘₐₓ (maximum velocity) is dependent on enzyme concentration, while an enzyme’s Kₘ (affinity measure) is not.
Therefore, heterozygous individuals would have a lower Vₘₐₓ.
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[each_answer] => A. The reaction rate would decrease due to a decrease in the reaction’s Vₘₐₓ.
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[each_answer] => B. The reaction rate would decrease due to an increase in the reaction’s Kₘ.
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[each_answer] => C. The reaction rate would increase due to an increase in the reaction’s Vₘₐₓ.
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[each_answer] => D. The reaction rate would increase due to a decrease in the reaction’s Kₘ.
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[quiz_unique_key] => 3413571627
[question] => Which of the following would best represent the outcome of an individual with the PKU mutation consuming a meal with a high phenylalanine content?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
Consuming a meal with high phenylalanine content would increase the concentration of phenylalanine significantly.
This would cause an increase in the [S] for the phenylalanine transaminase catalyzed reaction.
The increase in [S] for the phenylalanine transaminase catalyzed reaction will increase the rate of the reaction.
There would also be a significant increase in concentration of phenylalanine due to the PKU mutation preventing normal metabolism of phenylalanine. The passage states that PKU in fact results in a buildup of phenylalanine.
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[each_answer] => A. The phenylalanine transaminase catalyzed reaction rate would decrease, and the concentration of phenylalanine would decrease slightly.
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[each_answer] => B. The phenylalanine transaminase catalyzed reaction rate would increase, and the concentration of phenylalanine would increase significantly.
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[each_answer] => C. The phenylalanine transaminase catalyzed reaction rate would not be changed, and the concentration of phenylalanine would decreased significantly.
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[each_answer] => D. There is not enough available information to answer the question.
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Figure 1