UTP

**Structure and synthesis** - UTP = uracil + ribose + 3 phosphates (a ribonucleotide; the deoxy form dUTP is not incorporated into DNA). - De novo pyrimidine synthesis: Glutamine + CO2 + 2 ATP -> carbamoyl phosphate (CPS II, cytosolic; the rate-limiting, regulated step) -> + aspartate (aspartate transcarbamoylase) -> carbamoyl aspartate -> dihydroorotate (dihydroorotase) -> orotate (dihydroorotate dehydrogenase, mitochondrial) -> + PRPP (UMP synthase, which has orotate phosphoribosyltransferase and OMP decarboxylase activities) -> OMP -> UMP. - UMP -> UDP (UMP kinase) -> UTP (nucleoside diphosphate kinase). - UTP -> CTP via CTP synthetase (uses glutamine as the amino donor and ATP). - Regulation: UTP and CTP feedback-inhibit CPS II. ATP and PRPP activate it.

**Biochemical roles** - RNA synthesis: a substrate for RNA polymerases (uracil replaces thymine in RNA). - Glycogen synthesis: glucose-1-phosphate + UTP -> UDP-glucose + PPi (UDP-glucose pyrophosphorylase). UDP-glucose is the activated donor for glycogen synthase. - Galactose metabolism: galactose-1-phosphate uridyltransferase converts UDP-glucose + galactose-1-P to UDP-galactose + glucose-1-P. A deficiency causes classic galactosemia. - Glucuronidation: UDP-glucuronic acid is the donor for bilirubin conjugation (UGT1A1) and drug conjugation. Defects cause Gilbert syndrome (mild) and Crigler-Najjar syndrome (severe). - Other: UDP-sugars are used for glycoprotein and glycosaminoglycan synthesis, and UTP is also an extracellular signaling molecule via P2Y2 and P2Y4 receptors (Gq-coupled).

**Clinical correlations** - Orotic aciduria: a defect in UMP synthase (autosomal recessive) causes failure to make UMP, UTP and CTP. Findings include megaloblastic anemia that does not respond to B12 or folate, failure to thrive, and orotic acid crystalluria, with no hyperammonemia. Treatment is oral uridine (bypasses the block and feeds back to inhibit CPS II, reducing orotate production). - OTC deficiency vs orotic aciduria: both have elevated urinary orotic acid. OTC deficiency has hyperammonemia, because carbamoyl phosphate spills into the pyrimidine pathway. Orotic aciduria has normal ammonia. - Drugs affecting pyrimidine pathways: leflunomide and teriflunomide inhibit dihydroorotate dehydrogenase. 5-FU inhibits thymidylate synthase. Hydroxyurea inhibits ribonucleotide reductase. Methotrexate inhibits DHFR (depletes dTMP production). - Uridine triacetate is an antidote for 5-FU or capecitabine overdose or toxicity. - Ambiguity: on exams, "UTP" can occasionally also mean uridine triphosphate vs urinary tract pathology or "unable to proceed"; the biochemical meaning above is the most common in Step 1 contexts.

**High-yield pearls** - Purines are built on a ribose-phosphate scaffold (PRPP first). Pyrimidines build the ring first and then add PRPP (at the orotate step). - CPS I (mitochondrial, urea cycle, N-acetylglutamate activated, ammonia as nitrogen source) vs CPS II (cytosolic, pyrimidine synthesis, glutamine as nitrogen source, inhibited by UTP).