IMP (inosine monophosphate) is built up from PRPP through 10 enzymatic steps using formyl-THF (from folate_one_carbon) at two positions, glutamine amides at two more, glycine + aspartate + CO2 + bicarbonate at others. The most expensive biosynthesis in the cell. IMP → AMP (adenylosuccinate synthetase + lyase) or → GMP (IMPDH + GMP synthase). Drug targets: methotrexate depletes folate cofactors (slows steps 3 + 9 of purine synthesis + thymidylate synthesis); mycophenolate (MMF / Cellcept) inhibits IMPDH (selective T+B lymphocyte effect — these cells lack the salvage path and depend on de novo). Allopurinol's active metabolite oxypurinol also weakly inhibits PRPP synthetase upstream. Salvage path via HGPRT — deficient in Lesch-Nyhan (severe gout + self-mutilation behavior).
Organ Systems
immune-hematologic
Pathway Steps
phosphoribosyl-pyrophosphate → phosphoribosylamine — via PRPP amidotransferase (committed step; glutamine donor). PRPP amidotransferase is the committed, rate-limiting step, using glutamine as nitrogen donor. It is feedback-inhibited by the end products IMP/AMP/GMP and activated by PRPP — purine output balanced against need.
phosphoribosylamine → inosine-monophosphate — via multi-step (10 enzymes); 2× formyl-THF + 2× glutamine + glycine + aspartate. Ten steps build the purine ring directly onto ribose, consuming glycine, aspartate, two glutamines, CO₂ and two one-carbon units from N10-formyl-THF — why antifolates indirectly throttle purine synthesis. IMP is the common precursor of AMP and GMP.
inosine-monophosphate → amp — via adenylosuccinate synthetase + lyase. AMP synthesis from IMP uses GTP for energy and aspartate as nitrogen (via adenylosuccinate). Note the reciprocal cross-regulation: GTP drives AMP synthesis while ATP drives GMP synthesis, keeping the two nucleotide pools balanced.
inosine-monophosphate → gmp — via IMPDH (rate-limiting for GMP) — MYCOPHENOLATE TARGET; then GMP synthase. IMP dehydrogenase is rate-limiting for GMP and the target of mycophenolate (transplant immunosuppression) and ribavirin. Lymphocytes rely heavily on de-novo purines, which is why IMPDH inhibition is selectively immunosuppressive.