Expansion
Purines are built onto the ribose; pyrimidines are built first then attached
Expansion
Purine synthesis
- Built directly onto ribose-5-phosphate as PRPP
- Requires glycine, glutamine, aspartate, carbon dioxide and folate derivatives
- Rate limiting: PRPP amidotransferase
- Inhibited by methotrexate and 6-mercaptopurine
Pyrimidine synthesis
- The ring is made first, from carbamoyl phosphate and aspartate, then attached to PRPP
- Note that pyrimidine synthesis uses cytoplasmic carbamoyl phosphate synthetase II, distinct from the mitochondrial enzyme I of the urea cycle. In ornithine transcarbamylase deficiency, accumulated carbamoyl phosphate spills into this pathway, causing a raised urinary orotic acid, which is diagnostically useful
Ribonucleotide reductase converts ribonucleotides to deoxyribonucleotides for DNA, and is inhibited by hydroxycarbamide.
Thymidylate synthase makes dTMP and is inhibited by 5-fluorouracil; it requires folate, linking it to methotrexate.
This is why so many cytotoxic and immunosuppressive drugs are antimetabolites: rapidly dividing cells depend on nucleotide supply, so blocking these steps preferentially affects tumour, marrow, gut and hair.