IMP

**Note:** "IMP" is ambiguous. On USMLE it most often means **inosine monophosphate** (biochemistry). Other, less common uses: IMP = impression (clinical notes), IMP carbapenemase (imipenemase metallo-beta-lactamase in Gram-negative bacteria), and IMP = important/implant in some shorthand. The answer below focuses on inosine monophosphate.

**Pathway (de novo purine synthesis)** - Starts with ribose-5-phosphate → PRPP (via PRPP synthetase) → 5-phosphoribosylamine (via glutamine-PRPP amidotransferase, the rate-limiting step). - Building the purine ring on the ribose scaffold requires glycine, glutamine, aspartate, and N10-formyl-THF (two one-carbon units), and CO2. Mnemonic: "GAG CAF" (Glycine, Aspartate, Glutamine, CO2, And Formate/folate). - Result is **IMP**, the first compound with a complete purine ring (hypoxanthine base).

**Branch point** - IMP → AMP: requires **GTP** and aspartate (adenylosuccinate synthetase). - IMP → GMP: requires **ATP**, via IMP dehydrogenase (IMPDH) then GMP synthetase. - This reciprocal use of GTP for AMP and ATP for GMP balances the adenine and guanine pools.

**Regulation** - Glutamine-PRPP amidotransferase is inhibited by AMP, GMP, and IMP (end-product feedback inhibition). - PRPP is a positive regulator.

**Clinical and pharmacologic significance** - **Mycophenolate mofetil** inhibits IMP dehydrogenase, which blocks GMP synthesis. It selectively affects lymphocytes, which depend on de novo synthesis, so it is used as an immunosuppressant in transplant and lupus nephritis. - **Ribavirin** also inhibits IMPDH (it depletes GTP), which gives it antiviral activity (HCV, RSV). - **6-Mercaptopurine and azathioprine** are converted by HGPRT into thio-IMP, which inhibits de novo purine synthesis. Allopurinol or febuxostat (xanthine oxidase inhibitors) raise their toxicity, so reduce the dose. - **Methotrexate, trimethoprim** (via folate depletion) and **hydroxyurea** (ribonucleotide reductase inhibitor) impair nucleotide synthesis at other steps. Methotrexate is a DHFR inhibitor and reduces the N10-formyl-THF needed for IMP formation. - **Salvage pathway:** HGPRT converts hypoxanthine → IMP and guanine → GMP (using PRPP). **Lesch-Nyhan syndrome** is X-linked recessive HGPRT deficiency. It causes hyperuricemia and gout, intellectual disability, self-mutilation, dystonia and choreoathetosis, and orange "sand" in the diaper. The excess PRPP and failure to recycle purines drive increased de novo synthesis and uric acid production. - **Adenosine deaminase (ADA) deficiency** causes AR SCID through toxic buildup of dATP, which inhibits ribonucleotide reductase and impairs lymphocyte DNA synthesis. - **Degradation:** AMP → IMP → inosine → hypoxanthine → xanthine → uric acid (via xanthine oxidase).

**High-yield takeaways** 1. IMP is the first purine nucleotide formed and the branch point for AMP and GMP. 2. AMP synthesis needs GTP, and GMP synthesis needs ATP. 3. Mycophenolate and ribavirin inhibit IMPDH. 4. HGPRT salvages hypoxanthine to IMP, and deficiency causes Lesch-Nyhan syndrome. 5. 6-MP and azathioprine act through thio-IMP.