CPS I

**Reaction:** CO2 (as HCO3-) + NH4+ + 2 ATP -> carbamoyl phosphate + 2 ADP + Pi. This is the first and rate-limiting step of the urea cycle, and it takes place in the **mitochondrial matrix** of hepatocytes. Carbamoyl phosphate then combines with ornithine (via ornithine transcarbamylase, OTC) to form citrulline.

**Regulation:** - Activated allosterically by **N-acetylglutamate (NAG)**. NAG is made by NAG synthase from acetyl-CoA + glutamate, and arginine stimulates NAG synthase. - Increased amino acid catabolism raises glutamate, which raises NAG, which activates CPS I. This couples urea production to the nitrogen load.

**CPS I vs CPS II (high-yield comparison):** - CPS I: mitochondria; urea cycle; nitrogen source is free NH3; activated by NAG. - CPS II: cytosol; pyrimidine synthesis; nitrogen source is glutamine; inhibited by UTP and activated by PRPP. It is part of the multifunctional CAD enzyme complex.

**CPS I deficiency (autosomal recessive):** - Presents in neonates after protein feeding (day 1-3) with poor feeding, vomiting, lethargy, hypotonia, seizures, cerebral edema, and coma. It can also present later in life during catabolic stress. - Labs: **hyperammonemia, respiratory alkalosis (ammonia stimulates the respiratory center), low BUN, low citrulline and arginine, and normal or low orotic acid**. - Orotic acid is **normal or low** because carbamoyl phosphate is not made and so cannot spill into the pyrimidine pathway. In **OTC deficiency** (X-linked recessive, the most common urea cycle disorder), carbamoyl phosphate accumulates, leaves the mitochondria, and drives pyrimidine synthesis. Orotic acid is therefore **high**, with low BUN and low citrulline. - NAGS deficiency has the same biochemical picture as CPS I deficiency. The difference is that it responds to **N-carbamoylglutamate (carglumic acid)**, a NAG analog.

**Management:** - Acute: stop protein intake, give IV glucose to reduce catabolism, and give nitrogen scavengers (sodium benzoate, sodium phenylacetate/phenylbutyrate). Use hemodialysis for severe hyperammonemia. - Chronic: low-protein diet, **arginine or citrulline supplementation** (citrulline for CPS I and OTC deficiency, because it supplies a downstream urea cycle intermediate), and lactulose (traps NH4+ in the gut). Liver transplant is curative.

**Mnemonic:** In CPS I deficiency, the urea cycle is blocked at the first step, so no carbamoyl phosphate is made and orotic acid does not rise. Compare this with OTC deficiency, where carbamoyl phosphate accumulates and orotic acid rises.

**Clinical pearls:** - Ammonia toxicity: it depletes alpha-ketoglutarate, which impairs the TCA cycle in the brain. It also drives glutamine formation in astrocytes, causing osmotic swelling and cerebral edema. - Acquired hyperammonemia from liver failure or cirrhosis (hepatic encephalopathy) is treated with lactulose and rifaximin. - Valproate can cause hyperammonemia by inhibiting CPS I (it depletes NAG).