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HIV causes AIDS by infecting and destroying the immune system. The virus injects RNA into cells and reverse transcribes RNA into DNA using a viral enzyme called HIV-reverse transcriptase (RT, or Pol). RT functions as a DNA polymerase by making polymers of DNA from the viral RNA template. The standard treatment for HIV infection involves targeting the action of RT (in combination with other inhibitors). However, HIV has a high mutation rate, and can develop 'escape' mutations that reduce inhibitor effectiveness. Two such mutations are the K65R (Lys at position 65 is mutated to Arg) and K70E (Lys at position 70 is mutated to Glu) variants. The structures of deoxythymidine (dT) (normal substrate for DNA polymerase and HIV-reverse transcriptase) and AZT, a drug used in the treatment of HIV, are shown below. AZT works by serving as an alternative substrate for RT. Ideally, it is incorporated to the new DNA strand with comparable efficiency. dT AZT NH HO deoxythymidine 3'Azido-3-deonythymidine Wild-type (no mutations) К65R K70E Км (иМ) Км (иМ) Compound Kм (иМ) Deoxythymidine, dT 2.10 ±0.71 3'-azido-3'- Kcat (s*') Kcat (s*') Kcat (s*') 8.08 + 0.98 2.38 + 0.97 3.25 + 0.20 2.05 ± 0.32 7.70 ± 1.25 1.99 + 0.99 8.78 ± 0.24 2.18 + 1.66 1.05 ± 0.31 2.31 + 1.13 4.83 ± 0.97 deoxythymidine, AZT a. Based on the data, what is the catalytic efficiency for each enzyme with dT? b. Based on the data, what is the catalytic efficiency for each enzyme with AZT? c. Using that information, which variant is the most resistant to AZT? How do you know? d. In a clear argument, hypothesize how that mutation causes resistance to AZT. A complete answer will specify what causes the change catalytic efficiency (i.e change in KM, change in kcat or both), and how that specific amino acid change could cause that difference.

HIV causes AIDS by infecting and destroying the immune system. The virus injects RNA into cells and reverse transcribes RNA into DNA using a viral enzyme called HIV-reverse transcriptase (RT, or Pol). RT functions as a DNA polymerase by making polymers of DNA from the viral RNA template. The standard treatment for HIV infection involves targeting the action of RT (in combination with other inhibitors). However, HIV has a high mutation rate, and can develop 'escape' mutations that reduce inhibitor effectiveness. Two such mutations are the K65R (Lys at position 65 is mutated to Arg) and K70E (Lys at position 70 is mutated to Glu) variants. The structures of deoxythymidine (dT) (normal substrate for DNA polymerase and HIV-reverse transcriptase) and AZT, a drug used in the treatment of HIV, are shown below. AZT works by serving as an alternative substrate for RT. Ideally, it is incorporated to the new DNA strand with comparable efficiency. dT AZT NH HO deoxythymidine 3'Azido-3-deonythymidine Wild-type (no mutations) К65R K70E Км (иМ) Км (иМ) Compound Kм (иМ) Deoxythymidine, dT 2.10 ±0.71 3'-azido-3'- Kcat (s*') Kcat (s*') Kcat (s*') 8.08 + 0.98 2.38 + 0.97 3.25 + 0.20 2.05 ± 0.32 7.70 ± 1.25 1.99 + 0.99 8.78 ± 0.24 2.18 + 1.66 1.05 ± 0.31 2.31 + 1.13 4.83 ± 0.97 deoxythymidine, AZT a. Based on the data, what is the catalytic efficiency for each enzyme with dT? b. Based on the data, what is the catalytic efficiency for each enzyme with AZT? c. Using that information, which variant is the most resistant to AZT? How do you know? d. In a clear argument, hypothesize how that mutation causes resistance to AZT. A complete answer will specify what causes the change catalytic efficiency (i.e change in KM, change in kcat or both), and how that specific amino acid change could cause that difference.

Biochemistry
Biochemistry
9th Edition
ISBN:9781319114671
Author:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Publisher:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Chapter1: Biochemistry: An Evolving Science
Section: Chapter Questions
Problem 1P
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HIV causes AIDS by infecting and destroying the immune system. The virus injects RNA into cells and reverse transcribes RNA into DNA using a viral enzyme called HIV-reverse transcriptase (RT, or Pol). RT functions as a DNA polymerase by making polymers of DNA from the viral RNA template. The standard treatment for HIV infection involves targeting the action of RT (in combination with other inhibitors). However, HIV has a high mutation rate, and can develop 'escape' mutations that reduce inhibitor effectiveness. Two such mutations are the K65R (Lys at position 65 is mutated to Arg) and K70E (Lys at position 70 is mutated to Glu) variants. The structures of deoxythymidine (dT) (normal substrate for DNA polymerase and HIV-reverse transcriptase) and AZT, a drug used in the treatment of HIV, are shown below. AZT works by serving as an alternative substrate for RT. Ideally, it is incorporated to the new DNA strand with comparable efficiency. dT AZT NH HO deoxythymidine 3'Azido-3-deonythymidine Wild-type (no mutations) К65R K70E Км (иМ) Км (иМ) Compound Kм (иМ) Deoxythymidine, dT 2.10 ±0.71 3'-azido-3'- Kcat (s*') Kcat (s*') Kcat (s*') 8.08 + 0.98 2.38 + 0.97 3.25 + 0.20 2.05 ± 0.32 7.70 ± 1.25 1.99 + 0.99 8.78 ± 0.24 2.18 + 1.66 1.05 ± 0.31 2.31 + 1.13 4.83 ± 0.97 deoxythymidine, AZT a. Based on the data, what is the catalytic efficiency for each enzyme with dT? b. Based on the data, what is the catalytic efficiency for each enzyme with AZT? c. Using that information, which variant is the most resistant to AZT? How do you know? d. In a clear argument, hypothesize how that mutation causes resistance to AZT. A complete answer will specify what causes the change catalytic efficiency (i.e change in KM, change in kcat or both), and how that specific amino acid change could cause that difference.
Transcribed Image Text:HIV causes AIDS by infecting and destroying the immune system. The virus injects RNA into cells and reverse transcribes RNA into DNA using a viral enzyme called HIV-reverse transcriptase (RT, or Pol). RT functions as a DNA polymerase by making polymers of DNA from the viral RNA template. The standard treatment for HIV infection involves targeting the action of RT (in combination with other inhibitors). However, HIV has a high mutation rate, and can develop 'escape' mutations that reduce inhibitor effectiveness. Two such mutations are the K65R (Lys at position 65 is mutated to Arg) and K70E (Lys at position 70 is mutated to Glu) variants. The structures of deoxythymidine (dT) (normal substrate for DNA polymerase and HIV-reverse transcriptase) and AZT, a drug used in the treatment of HIV, are shown below. AZT works by serving as an alternative substrate for RT. Ideally, it is incorporated to the new DNA strand with comparable efficiency. dT AZT NH HO deoxythymidine 3'Azido-3-deonythymidine Wild-type (no mutations) К65R K70E Км (иМ) Км (иМ) Compound Kм (иМ) Deoxythymidine, dT 2.10 ±0.71 3'-azido-3'- Kcat (s*') Kcat (s*') Kcat (s*') 8.08 + 0.98 2.38 + 0.97 3.25 + 0.20 2.05 ± 0.32 7.70 ± 1.25 1.99 + 0.99 8.78 ± 0.24 2.18 + 1.66 1.05 ± 0.31 2.31 + 1.13 4.83 ± 0.97 deoxythymidine, AZT a. Based on the data, what is the catalytic efficiency for each enzyme with dT? b. Based on the data, what is the catalytic efficiency for each enzyme with AZT? c. Using that information, which variant is the most resistant to AZT? How do you know? d. In a clear argument, hypothesize how that mutation causes resistance to AZT. A complete answer will specify what causes the change catalytic efficiency (i.e change in KM, change in kcat or both), and how that specific amino acid change could cause that difference.
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