arginase

**Reaction:** Arginine + H2O → Ornithine + Urea. Ornithine is shuttled back into the mitochondria by the ORNT1 transporter to continue the cycle. Urea is excreted by the kidneys. Arginase requires Mn2+ as a cofactor.

**Isoforms:** - Arginase 1 (ARG1): cytosolic, mainly in the liver; the urea cycle enzyme. Deficiency causes disease. - Arginase 2 (ARG2): mitochondrial, extrahepatic (kidney, prostate, intestine, macrophages). It regulates arginine for nitric oxide (NO) and polyamine synthesis. It is not part of the hepatic urea cycle.

**Urea cycle order (mnemonic: "Ordinarily, Careless Crappers Are Also Frivolous About Urination"):** Ornithine → Carbamoyl phosphate (CPS I) → Citrulline (OTC) → Argininosuccinate (argininosuccinate synthetase) → Arginine (argininosuccinate lyase) → Ornithine + Urea (arginase). Mitochondrial steps: CPS I and OTC. Cytosolic steps: ASS, ASL, and arginase.

**Arginase deficiency (hyperargininemia):** - Autosomal recessive, ARG1 mutation. - Clinical features: usually appear at age 1–3 years, later than other urea cycle defects. These include progressive spastic diplegia/paraparesis (the hallmark and distinguishing feature), developmental regression, seizures, and growth failure. Neonatal hyperammonemic crisis is uncommon. - Labs: markedly elevated plasma arginine, mildly elevated or intermittent ammonia, and elevated orotic acid in some patients. Urine amino acid analysis may show arginine and other dibasic amino acids. - Why milder hyperammonemia: arginine is still excreted in the urine, and it carries nitrogen out as a "waste" route, which partly protects against severe ammonia accumulation. Arginine accumulation itself is thought to be neurotoxic, causing guanidino compound production and spasticity. - Treatment: low-protein diet, essential amino acid supplementation, nitrogen scavengers (sodium phenylbutyrate or glycerol phenylbutyrate), and avoiding arginine supplements. This contrasts with other urea cycle defects such as ASS or ASL deficiency, where arginine is supplemented. Enzyme replacement (pegzilarginase) has been developed.

**Buzzwords and distinctions:** - Other urea cycle disorders (OTC, CPS I) present with neonatal hyperammonemia, lethargy, vomiting, and cerebral edema. Arginase deficiency instead presents with spasticity. - OTC deficiency (X-linked recessive, the most common urea cycle disorder): high orotic acid and low BUN. - Arginase deficiency: high arginine, with spastic diplegia.

**Other clinical significance:** - Arginase competes with nitric oxide synthase (NOS) for arginine. Increased arginase activity reduces NO production and contributes to endothelial dysfunction, asthma (airway hyperreactivity), and sickle cell disease (low arginine bioavailability, pulmonary hypertension). - Macrophage polarization: M2 macrophages upregulate arginase 1 (tissue repair, fibrosis, immunosuppression), whereas M1 macrophages upregulate iNOS (microbial killing). Arginase 1 in tumor-associated myeloid cells depletes arginine and suppresses T-cell function. - Arginase is a diagnostic marker for hepatocellular carcinoma on immunohistochemistry (hepatocyte-specific marker, along with HepPar-1). - Ornithine produced by arginase is a precursor for polyamines (via ornithine decarboxylase) and proline.