B₁₂/Folate Problem set

Question 6: Folate in the synthesis of dTMP

Human thymidylate synthase can be effectively and specifically inhibited by administration of:

A.	uridylate (dUMP)
B.	trimethoprim
C.	5-fluorouracil (5-FU) 5-FU is the answer, but the actual inhibitor is 5-fluorouridylate (F-dUMP in the notes). 5-fluorouracil mimics the size and shape of thymine. What then happens is that salvage enzymes reattach a ribose and phosphate group to it to make F-dUMP. This compound, in turn, inhibits thymidylate synthase because of its resemblance to dTMP, the product of the thymidylate synthase reaction. What we therefore have here is the product (or, in this case, a fake product) feedback inhibiting its own synthesis. Now on to other drugs...
D.	sulfanilamide (a sulfa drug)
E.	methotrexate (MTX)