amidophosphoribosyltransferase

**Reaction:** PRPP + glutamine → 5-phosphoribosylamine + glutamate + pyrophosphate. This is the first committed step and the main regulatory point of de novo purine biosynthesis (which then builds IMP, the precursor of AMP and GMP).

**Regulation (high-yield):** - Activated by PRPP (substrate availability). PRPP levels are controlled by PRPP synthetase (ribose-5-phosphate + ATP → PRPP). - Feedback inhibited by the end-products AMP, GMP, and IMP. - PRPP synthetase is also inhibited by purine nucleotides.

**Clinical significance:** - **Gout / hyperuricemia:** Increased PRPP synthetase activity (X-linked) or increased PRPP availability drives purine overproduction and uric acid accumulation. - **Lesch-Nyhan syndrome (HGPRT deficiency):** Failure of purine salvage leaves excess PRPP unused. The excess PRPP activates amidophosphoribosyltransferase, so de novo synthesis increases. The result is hyperuricemia, gout, self-mutilation, intellectual disability, dystonia/choreoathetosis, and orofacial dyskinesia. - **Von Gierke disease (G6Pase deficiency):** More glucose-6-phosphate is shunted through the pentose phosphate pathway. This raises ribose-5-phosphate and PRPP, which increases purine synthesis and uric acid. Lactate and ketones also compete with urate for renal excretion. - **Pharmacology:** 6-mercaptopurine (6-MP) and azathioprine are converted by HGPRT to thio-IMP, which inhibits amidophosphoribosyltransferase. Mycophenolate inhibits IMP dehydrogenase, a later step. Allopurinol/febuxostat inhibit xanthine oxidase and do not act on this enzyme. - **Glutamine analogs** (azaserine, 6-diazo-5-oxo-L-norleucine) inhibit glutamine-dependent amidotransferases. Folate antagonists (methotrexate) impair later purine steps, which need N10-formyl-THF.

**Board pearls:** - Don't confuse it with carbamoyl phosphate synthetase II (CPS II), the rate-limiting enzyme of **pyrimidine** synthesis. CPS II is activated by PRPP and inhibited by UTP. - Don't confuse it with ribonucleotide reductase, which makes deoxyribonucleotides and is inhibited by hydroxyurea. - Purine synthesis builds the base on a ribose-5-phosphate scaffold (PRPP). Pyrimidine synthesis builds the ring first and then adds PRPP. - Purine ring atom sources: glycine, aspartate, glutamine (N3 and N9), CO2, and N10-formyl-THF (C2 and C8).