Question

Which data suggest that the differences in Compound 1 metabolism between the variant and wild-type CYP2C9 enzymes are NOT due to changes in the binding affinity toward Compound 1?

A. Compound 1 is still eliminated from the body of patients expressing the CYP2C9*3 allele.
B. The KM values for the variant enzymes do not differ significantly from the wild-type enzyme.
C. The amino acid substitutions at positions 144 and 359 do not change the binding pocket of the variant enzymes.
D. The side chains of the amino acid residues at positions 144 and 359 are charged at physiological pH.

Answer 1

Data suggesting that differences in CYP2C9 metabolism for Compound 1 are not due to changes in binding affinity may include mutations that don't significantly affect stability but alter enzyme activity or specificity, as well as alterations in compounds leading to changes in metabolism and permeability without corresponding changes in binding.

Step-by-step explanation:

The differences in Compound 1 metabolism between the variant and wild-type CYP2C9 enzymes are suggested not to be due to changes in binding affinity if mutations don't impact the stability significantly. Instead, these differences could be due to other factors such as changes in enzyme kinetics or alterations in the metabolic pathway.

For example, mutations of certain residues that form the binding sub-site, which could affect discrimination by the enzyme, provide insight into the structural intricacies that govern substrate metabolism but do not necessarily reflect a change in binding affinity as much as changes in substrate specificity or enzyme activity.

Furthermore, when comparing compounds with altered physiochemical properties, such as methylated or rigidified analogs, effects on metabolism, stability, and permeability can be observed without proportionate changes in binding affinity, suggesting that modifications at certain positions can disrupt interactions critical for metabolism but not necessarily for binding.