Folate donates one carbon units for thymidine and purine synthesis
Expansion
Function: tetrahydrofolate carries one carbon units for the synthesis of thymidine and purines, and for the conversion of homocysteine to methionine. Blocking it therefore blocks DNA synthesis, which is why deficiency and antifolates both cause megaloblastic change.
The antifolates, each acting at a different point
- Methotrexate - inhibits dihydrofolate reductase in human cells
- Trimethoprim - inhibits bacterial dihydrofolate reductase, with far greater affinity for the bacterial enzyme
- Sulphonamides - inhibit dihydropteroate synthase, an earlier bacterial step. Combined with trimethoprim as co-trimoxazole for sequential blockade
- Pyrimethamine - protozoal dihydrofolate reductase, used in toxoplasmosis
- Phenytoin and alcohol impair folate absorption and metabolism
“Folinic acid rescues, folic acid does not.” Folinic acid (leucovorin) is already reduced, so it bypasses dihydrofolate reductase and can rescue human cells after high dose methotrexate. Folic acid cannot, because it still requires the blocked enzyme.
Methotrexate practicalities: given weekly, not daily, which is a recognised fatal prescribing error; taken with folic acid on a different day; monitored with full blood count, liver and renal function; and contraindicated in pregnancy.
Neural tube defects: 400 micrograms of folic acid daily preconception and to 12 weeks, or 5 mg with previous affected pregnancy, diabetes, obesity, antiepileptics or coeliac disease.