Nitrogen Metabolism and the Urea Cycle PDF

🚽 10/2/24, 3:00 PM Nitrogen Metabolism and the Urea Cycle Urine and Ammonia Urine is acidic and traps ammonia as the ammonium ion, decreasing the toxicity of the ammonia. Ammonia is a lot...

🚽 10/2/24, 3:00 PM Nitrogen Metabolism and the Urea Cycle Urine and Ammonia Urine is acidic and traps ammonia as the ammonium ion, decreasing the toxicity of the ammonia. Ammonia is a lot more toxic than the ammonium ion. Glutaminase and AsparaginaseNetMessage Glutaminase: removes nitrogen and generates glutamate and glutamine, which can be thought of as an intracellular carrier of nitrogen. Asparaginase: not typically an issue, but it is an enzyme that exists. L and D Amino Acid Oxidase Enzymes ⚖️ L Amino Acid Oxidase: requires FMN (flavine mononucleotide) and generates peroxide. D Amino Acid Oxidase: uses FAD and generates peroxide. This enzyme is important for breaking down D amino acids, which are typically found in bacterial infections. The Glucose-Alanine Cycle (Cahill Cycle) 🔄 The glucose-alanine cycle is a way to conserve glucose backbones. It involves: Converting alanine to pyruvate Converting pyruvate back to glucose in the liver Using glucose in the brain and red blood cells Preventing glucose from being used in muscle cells, where it would be broken down into fatty acids and ketone bodies The Importance of Catalase 🔋 Catalase is an enzyme found in peroxisomes that detoxifies peroxide generated by L and D amino acid oxidases. Ammonia Toxicity ☠️ Ammonia levels greater than 10 micrograms per liter are toxic to cells. The ammonium ion is less toxic, with a toxic level of around half a milligram. Fortunately, there is a 100-fold higher concentration of ammonium ion than ammonia under physiological conditions. Urea Cycle 💪 A complete block in any step of the urea cycle is incompatible with life. Urea Cycle Defects Disease Hyperammonemia leading to ammonia intoxication Patients are intolerant to protein ingestion and show mental and CNS deficiencies Treatment involves a low protein diet and, in some cases, Alpha Keto Glutarate https://www.turbolearn.ai/content/5d0b2cf2-d80c-4979-a559-5145411a176c 1/4  🤔 10/2/24, 3:00 PM Nitrogen Metabolism and the Urea Cycle Why Alpha Keto Glutarate is Used in Hyperammonemia Treatment Alpha Keto Glutarate is used because it can transaminate the nitrogen to form glutamate, an intracellular carrier of nitrogen. Urea Cycle Enzymes 🧮 Enzyme Function Carbamylphosphate synthetase Takes free ammonium and converts it to a compound for entry into the TCA cycle (analogous to PDH in the TCA cycle) N Acetylglutamate An important compound that plays a role in the urea cycle (more information to come) Note: The urea cycle is split between the mitochondrion and the cytosol.## Urea Cycle 🌡️ The urea cycle is a crucial process that occurs in the liver, where nitrogen from ammonia is converted into urea, which is then excreted out of the body. Location of Enzymes 📍 The first two enzymes of the urea cycle are located in the mitochondrial matrix, while the remaining three enzymes are located in the cytosol. Carbonyl Phosphate Synthetase 1 (CPS 1) 🔍 CPS 1 is the first enzyme of the urea cycle, which catalyzes the reaction between bicarbonate and ammonium ion to form carbonyl phosphate. "Carbonyl phosphate is an activated form of urea, with a phosphate group on one end and a nitrogen group on the other." Ornithine Transcarbamylase 🔄 Ornithine transcarbamylase is the second enzyme of the urea cycle, which catalyzes the reaction between ornithine and carbamyl phosphate to form citrulline. Urea Cycle Reactions 🔄 The following table summarizes the reactions of the urea cycle: Enzyme Reactants Products CPS 1 Bicarbonate, Ammonium ion Carbonyl phosphate Ornithine Transcarbamylase Ornithine, Carbamyl phosphate Citrulline Arginosuccinate Synthetase Citrulline, Aspartate Arginosuccinate Arginosuccinate Lyase Arginosuccinate Arginine Arginase Arginine Urea Hyperammonemia ❗️ https://www.turbolearn.ai/content/5d0b2cf2-d80c-4979-a559-5145411a176c 2/4 10/2/24, 3:00 PM Nitrogen Metabolism and the Urea Cycle Hyperammonemia is a condition characterized by high levels of ammonia in the blood. Deficiencies in enzymes of the urea cycle can lead to hyperammonemia. Activation of the Urea Cycle 💪 The urea cycle is activated by the flow of nitrogen, which is regulated by the enzyme N-Acetylglutamate Synthetase. This enzyme generates N-Acetylglutamate, which activates Carbonyl Phosphate Synthetase 1. Urea Precursors 📦 The urea precursors are the compounds that provide the nitrogen for the urea cycle. These include: Aspartate Free ammonium ion Carbamyl phosphate## Hyperammonemia 🤕 Urea Cycle The urea cycle consists of two enzymes: Carbamylphosphate Synthetase 1 (CPS 1) and Ornithine Transcarbamylase (OTC) CPS 1 is the rate-limiting enzyme, regulated by N-Acetylglutamate Process: 1. Ammonium ion + Bicarbonate → Carbamylphosphate (via CPS 1) 2. Carbamylphosphate → Citrulline (via OTC) 3. Citrulline → Argininosuccinate (via Argininosuccinate Synthetase) 4. Argininosuccinate → Arginine (via Argininosuccinate Lyase) 5. Arginine → Urea (via Arginase) 6. Urea → Ornithine (via Arginase) Hyperammonemia Diagnosis Elevated ammonia levels Decreased BUN levels Blood glutamine levels are increased Enzyme Deficiencies Ornithine Transcarbamylase (OTC) Deficiency Symptoms: Hyperammonemia Elevated carbamylphosphate levels Elevated orotic acid levels (due to artificial stimulation of pyrimidine biosynthesis) Diagnosis: Orotic acid urea Carbamylphosphate Synthetase 1 (CPS 1) Deficiency https://www.turbolearn.ai/content/5d0b2cf2-d80c-4979-a559-5145411a176c 3/4 10/2/24, 3:00 PM Nitrogen Metabolism and the Urea Cycle Symptoms: Hyperammonemia Decreased carbamylphosphate levels Decreased orotic acid levels Diagnosis: No orotic acid urea Clinical Signs and Symptoms Central edema Lethargy Convulsions Coma Death Note: Ammonia can cross the blood-brain barrier, leading to central edema. Summary Enzyme Deficiency Symptoms Diagnosis OTC Deficiency Hyperammonemia, Elevated Carbamylphosphate, Elevated Orotic Acid Orotic Acid Urea CPS 1 Deficiency Hyperammonemia, Decreased Carbamylphosphate, Decreased Orotic Acid No Orotic Acid Urea https://www.turbolearn.ai/content/5d0b2cf2-d80c-4979-a559-5145411a176c 4/4