4) Methotrexate is an inhibitor of the enzyme dihydrofolate reductase and is oft

Question

4) Methotrexate is an inhibitor of the enzyme dihydrofolate reductase and is often used as a chemotherapy agent for treatment of leukemia, non-Hodekins lymphoma, and some forms of breast cancer, among other diseases. Methotrexate has three ionizable groups: two hydroxyl groups with pKas of 3.1 and 4.4, respectively, and a nitrogen with a pKof 5.6. The structure of methotrexate and the three ionization reactions are shown in the figure below. If methorexate is dissolved in physiological saline at a pH of 7.2, what will the total or net charge on this molecule be? For full credit, describe or explain how you arrived at your answer; remember to account for the charge contribution from each ionizable group. (3 points) HaN 0% . K-3. a 4.4 HN CH NH CHs +H

Explanation / Answer

When the PKa of an ionizable group is LESS than the PH at which the molecule is kept, then the ionizable group of that molecule donates a proton. And when the PKa of an ionizable group is MORE than the PH at which the molecule is kept, then the ionizable group of that molecule accepts a proton.

       Thus, PH > PKa ; Donates a Proton.

              PH < PKa ; Accepts a Proton.

So, here in case of Methotrexate, at PH = 7.2, the OH group with PKa= 3.1, will donate the proton and will be negatively charged, similarly the OH group with PKa= 4.1, will also donate the proton and acquire negative charge, whereas, the nitrogen (here, NH+) with PKa= 5.6, will also donate the proton and will now acquire a neutral charge. So, at PH = 7.2, the methotrexate molecule will attain a total of two Negative charges (2 ’-ve’) on it.

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