inosine monophosphate

**Structure/role:** IMP is a purine nucleotide with the base hypoxanthine attached to ribose-5-phosphate. It is the first product of de novo purine synthesis with a complete purine ring and serves as the common precursor to AMP and GMP.

**De novo synthesis (occurs mainly in liver, cytosol):** - Ribose-5-phosphate -> PRPP (via PRPP synthetase). - PRPP + glutamine -> 5-phosphoribosylamine, catalyzed by glutamine-PRPP amidotransferase (the committed, rate-limiting step). It is inhibited by AMP, GMP, and IMP (feedback) and activated by PRPP. - The purine ring is built on the ribose scaffold. Sources of atoms: glycine (C4, C5, N7), aspartate (N1), glutamine (N3, N9), N10-formyl-THF (C2, C8), and CO2 (C6). - The final steps are formation of the ring by IMP cyclohydrolase, which gives IMP. The steps use the folate pathway, so inhibition of folate metabolism (methotrexate, trimethoprim) impairs purine synthesis.

**Branch point:** - IMP -> AMP: adenylosuccinate synthetase (uses GTP and aspartate), then adenylosuccinate lyase (releases fumarate). - IMP -> GMP: IMP dehydrogenase (IMPDH; oxidizes IMP to XMP using NAD+), then GMP synthetase (uses ATP and glutamine). - Reciprocal regulation: GTP drives AMP synthesis and ATP drives GMP synthesis, which balances the pools. AMP inhibits the AMP branch, and GMP inhibits the GMP branch.

**Salvage pathway:** - HGPRT converts hypoxanthine + PRPP -> IMP and guanine + PRPP -> GMP. APRT converts adenine + PRPP -> AMP. - HGPRT deficiency causes Lesch-Nyhan syndrome (X-linked recessive): hyperuricemia/gout, intellectual disability, self-mutilation, dystonia/choreoathetosis. Excess PRPP and loss of feedback inhibition increase de novo synthesis. Treat with allopurinol/febuxostat for urate.

**Catabolism:** AMP -> IMP (AMP deaminase) -> inosine -> hypoxanthine -> xanthine -> uric acid (xanthine oxidase). GMP -> guanine -> xanthine -> uric acid. ADA deficiency (AMP/adenosine/dATP accumulation) causes an AR form of SCID by toxicity to lymphocytes (dATP inhibits ribonucleotide reductase).

**Drug associations (high yield):** - Mycophenolate mofetil: inhibits IMPDH (reversible), so it blocks GMP synthesis. It is selective for lymphocytes, which rely on de novo synthesis. It is used in transplant and lupus nephritis. Adverse effects: GI upset, pancytopenia, teratogenicity. - Ribavirin: also inhibits IMPDH (depletes GTP). It is used for HCV and RSV. Adverse effects: hemolytic anemia, teratogenicity. - Azathioprine -> 6-mercaptopurine (6-MP) -> thio-IMP, which inhibits de novo purine synthesis. 6-MP is inactivated by xanthine oxidase, so allopurinol raises levels (reduce the dose by about 75%). Toxicity is also increased with TPMT deficiency. - Methotrexate, trimethoprim, and other antifolates indirectly impair IMP formation (reduced N10-formyl-THF). - Hydroxyurea inhibits ribonucleotide reductase (deoxynucleotides), not de novo IMP formation.

**Pearls:** Purine synthesis builds the base on PRPP (de novo), while pyrimidine synthesis builds the ring first (orotate) and then attaches PRPP. IMP is a purine (never a pyrimidine) nucleotide. Do not confuse IMP with inosine (the nucleoside, no phosphate) or with hypoxanthine (the free base).