Part II – Enzyme Activity
Dr. Ryder learns that the difference in patient reaction to the drug probably has something to do with how the drug is naturally metabolized in the body to be removed as waste. After searching the scientific literature, she learns that the drug 6-MP can either be converted to the active form, TGN nucleotides, or can be inactivated with the help of the TPMT enzyme (thiopurine methyltransferase). Within each patient who takes the drug, both processes are occurring and they compete with each other.
Figure 1. Flow Chart
Flow chart showing activiation and inactivation paths of the drug 6-MP. (Enlargement)
Source:
Since the therapy aims to harm rapidly replicating cells without overly impacting normal ones, it is important that excess drug is inactivated. Dr. Ryder decides to see how levels of the TPMT enzyme activity might vary between people.
She reviews the research papers that have been published about the TPMT enzyme and finds an interesting graph. From a study of 298 randomly selected Caucasian individuals, researchers found the following levels of TPMT enzyme activity:
Figure 2. Simplified Results.
Simplified bar graph showing results from a study of 298 randomly selected Caucasian patients. (Enlargement)
Source: Simplified graph patterned after the top panel of Figure 2 in: Weinshilboum, R.M., and S. Sladek (1980) Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity. American Journal of Human Genetics 32:651–662.
Questions
2a. If Dr. Ryder had 10 Caucasian patients in the next month, how many would you predict to have each of the TPMT enzyme activity levels, based on the graph above?
- Low:
- Medium:
- High:
Would you expect the actual/observed number of patients to be different? Why might there be differences?
2b. Each individual inherits two copies of the gene for the enzyme, one from each parent. Dr. Ryder suspects that variation in enzyme activity level is controlled by two different versions (alleles) of that gene. Does this graph (and the number of phenotypes) suggest that enzyme activity levels are based on a dominant/recessive or a codominant pattern of inheritance? Explain your answer.
2c. Which bar (low, medium, or high) represents individuals who might be homozygous for a “low enzyme activity’” version of the gene? Which bar represents individuals who might be homozygous for a “high enzyme activity” version of the gene? Which bar represents heterozygotes?
2d. Answer the question: “How does enzyme activity level vary among the patients examined?” In your answer, be sure to include supporting data from the graph above. Explain how these data support your conclusion.
2e. Challenge question: The actual graph (below) showed much more detail. Why do you think that there is more variation between patients than shown in the simplified graph?
Figure 3. Histogram
RBC TPMT frequency distribution histogram for 298 randomly selected Caucasian subjects. (Enlargement)
Source: Histogram drawn after top panel of Figure 2 in: Weinshilboum, R.M., and S. Sladek (1980) Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity. American Journal of Human Genetics 32:651–662.
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