CPS II
Summary
CPS II (carbamoyl phosphate synthetase II) is the cytosolic, rate-limiting enzyme of de novo pyrimidine synthesis. It uses glutamine + CO2 + 2 ATP to make carbamoyl phosphate; it is activated by PRPP and ATP and inhibited by UTP. It is distinct from mitochondrial CPS I (urea cycle), which uses ammonia and is activated by N-acetylglutamate.
Detail
**Reaction:** Glutamine + 2 ATP + HCO3- (CO2) → carbamoyl phosphate + glutamate + 2 ADP + Pi. CPS II is the committed, rate-limiting step of pyrimidine synthesis.
**Location:** Cytosol. In humans it is part of the multifunctional CAD protein (C = CPS II, A = Aspartate transcarbamoylase, D = Dihydroorotase), which catalyzes the first 3 steps of the pathway.
**Pathway context:** Carbamoyl phosphate + aspartate (via aspartate transcarbamoylase) → carbamoyl aspartate → (dihydroorotase) → dihydroorotate → (dihydroorotate dehydrogenase, mitochondrial) → orotic acid → (UMP synthase: orotate phosphoribosyltransferase + OMP decarboxylase) → UMP → UDP/UTP → CTP (CTP synthetase) and dTMP (thymidylate synthase).
**Regulation:** - Activated by PRPP and ATP. - Inhibited by UTP (end-product feedback inhibition).
**CPS I vs CPS II (classic high-yield comparison):**
| | CPS I | CPS II | |---|---|---| | Location | Mitochondria | Cytosol | | Pathway | Urea cycle | Pyrimidine synthesis | | N source | Free ammonia (NH3/NH4+) | Glutamine amide group | | Activator | N-acetylglutamate (NAG) | PRPP (and ATP) | | Inhibitor | none specific | UTP |
**Clinical correlations:** - **Hyperammonemia (e.g., OTC deficiency, the most common urea cycle disorder, X-linked):** Ornithine transcarbamylase deficiency causes mitochondrial carbamoyl phosphate to accumulate. It spills into the cytosol and feeds pyrimidine synthesis, bypassing CPS II regulation. This produces **orotic aciduria** with **increased orotic acid** and **decreased BUN**, plus hyperammonemia. Contrast with hereditary orotic aciduria (UMP synthase deficiency), which has **no hyperammonemia** and presents with megaloblastic anemia unresponsive to B12/folate. Treat with uridine. - **Differentiating OTC deficiency from orotic aciduria:** OTC deficiency has hyperammonemia; orotic aciduria does not. - **Drugs:** Leflunomide and teriflunomide inhibit dihydroorotate dehydrogenase (not CPS II). Methotrexate, 5-FU, and hydroxyurea inhibit later steps of nucleotide synthesis (dTMP synthesis and ribonucleotide reductase). Do not confuse these targets with CPS II. - **Cancer:** CAD is upregulated in rapidly proliferating cells. It is phosphorylated and activated by mTORC1 (via S6K1) and MAPK signaling, linking growth signals to nucleotide supply.
**Mnemonic:** CPS "II" = "2" → pyrimidines are "CUT the PYe" (Cytosine, Uracil, Thymine). CPS I = "1" in the urea cycle, which occurs in the mitochondria (**I**ntra-mitochondrial).
Sources
- First Aid for the USMLE Step 1 (Biochemistry: Nucleotide synthesis; Urea cycle)
- Lippincott Illustrated Reviews: Biochemistry (Pyrimidine synthesis and degradation)
- Harper's Illustrated Biochemistry (Metabolism of purine and pyrimidine nucleotides)
- Pathoma / Sketchy Medical / Boards and Beyond: Biochemistry (Pyrimidine synthesis; Orotic aciduria vs OTC deficiency)
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