Which enzyme catalyzes the first committed step of the urea cycle, and what is its substrate?

Explanation

## The First Committed Step of Urea Cycle **Key Point:** Carbamoyl phosphate synthetase I (CPS I) catalyzes the first committed step of the urea cycle, combining ammonia (NH₃) and bicarbonate (HCO₃⁻) in the presence of 2 ATP molecules to form carbamoyl phosphate. ### Reaction Details $$\text{NH}_3 + \text{HCO}_3^- + 2\text{ATP} \xrightarrow{\text{CPS I}} \text{Carbamoyl phosphate} + 2\text{ADP} + P_i$$ **High-Yield:** CPS I is a mitochondrial enzyme and is the rate-limiting enzyme of the urea cycle. It is activated by N-acetylglutamate (NAG), which is a key allosteric regulator. ### Why CPS I is the "First Committed" Step - Carbamoyl phosphate produced by CPS I is committed to urea synthesis (not to pyrimidine synthesis, which uses CPS II in the cytoplasm). - This is the point of no return in the pathway. - Deficiency of CPS I leads to severe hyperammonemia and is one of the most severe urea cycle disorders. **Clinical Pearl:** CPS I deficiency presents with neonatal hyperammonemia, lethargy, seizures, and cerebral edema. Unlike OTC deficiency, it shows no sex-linked inheritance pattern. ### Subsequent Steps (for context) 1. CPS I: NH₃ + HCO₃⁻ → Carbamoyl phosphate 2. OTC: Carbamoyl phosphate + Ornithine → Citrulline 3. Argininosuccinate synthetase: Citrulline + Aspartate → Argininosuccinate 4. Argininosuccinate lyase: Argininosuccinate → Arginine + Fumarate 5. Arginase: Arginine → Urea + Ornithine