Nitrogen Metabolism and Urea Cycle Processes PDF

Chemical Reactions in Nitrogen Metabolism Urine and Ammonia Urine is acidic and traps ammonia as the ammonium ion, decreasing the toxicity of ammonia. Ammonia is more toxic than the ammonium ion....

Chemical Reactions in Nitrogen Metabolism Urine and Ammonia Urine is acidic and traps ammonia as the ammonium ion, decreasing the toxicity of ammonia. Ammonia is more toxic than the ammonium ion. Enzymes in Nitrogen Metabolism Glutaminase: removes nitrogen and generates glutamate and glutamine, an intracellular carrier of nitrogen. Glutamine Synthetase: mentioned earlier in the lecture. Asparaginase: not significant in terms of enzyme issues. L-Amino Acid Oxidase and D-Amino Acid Oxidase L-Amino Acid Oxidase: Deamination reaction that generates α-keto acid and ammonium. Requires FMN (Flavine Mononucleotide) to capture protons. Generates peroxide. D-Amino Acid Oxidase: https://www.turbolearn.ai/content/a18feabb-9819-4296-a5e6-c8a53090103f 10/2/24, 11 35 AM Page 1 of 8 :  Breaks down D-amino acids, commonly found in bacterial infections. Generates peroxide. Occurs in the peroxisome, where catalase can detoxify the peroxide. The Glucose-Alanine Cycle (Cahill Cycle) Alanine is converted to pyruvate, then to glucose in the liver. Glucose is transported to the brain and red blood cells, not the muscle cells. Muscle cells use fatty acids and ketone bodies for energy. Toxicity of Ammonia “"Ammonia levels greater than 10 micrograms per liter are toxic to cells."” Ammonium ion is less toxic than ammonia, with a concentration about half a milligram. The body typically takes in 100 grams of protein, including 16.5 grams of nitrogen. The Urea Cycle Complete Block in the Urea Cycle Incompatible with life. Leads to hyperammonemia and ammonia intoxication. https://www.turbolearn.ai/content/a18feabb-9819-4296-a5e6-c8a53090103f 10/2/24, 11 35 AM Page 2 of 8 :  Patients may be intolerant to protein ingestion and show mental and CNS deficiencies. Treatment of Hyperammonemia Alpha-Ketoglutarate can be used to transaminate nitrogen to glutamate, an intracellular carrier of nitrogen. Urea Cycle Enzymes Enzyme Function Carbamylphosphate Converts ammonium to a compound for entry into Synthetase (CPS) the TCA cycle N-Acetylglutamate Important compound in the urea cycle Note: The urea cycle is split between the mitochondrion and the cytosol.## Urea Cycle The urea cycle is a process by which the body eliminates excess nitrogen in the form of urea. Enzymes of the Urea Cycle The urea cycle involves five enzymes: Carbonyl Phosphate Synthetase 1 (CPS 1): located in the mitochondrial matrix Ornithine Transcarbamylase (OTCPSase): located in the mitochondrial matrix https://www.turbolearn.ai/content/a18feabb-9819-4296-a5e6-c8a53090103f 10/2/24, 11 35 AM Page 3 of 8 :  Arginosuccinate Synthetase: located in the cytosol Arginosuccinate Lyase: located in the cytosol Arginase: located in the cytosol Carbonyl Phosphate Synthetase 1 (CPS 1) “"I think of it as an activated urea." CPS 1 takes bicarbonate and ammonium ion to form carbonyl phosphate with a nitrogen.” Ornithine Transcarbamylase (OTC) “OTC takes ornithine and carbamyl phosphate to form citrulline.” Citrulline and Ornithine Citrulline: an amino acid not found in proteins, used in the urea cycle Ornithine: an amino acid not found in proteins, used in the urea cycle Both citrulline and ornithine can cross the mitochondrial membrane. Arginosuccinate Synthetase and Arginosuccinate Lyase Arginosuccinate Synthetase: takes citrulline and aspartate to https://www.turbolearn.ai/content/a18feabb-9819-4296-a5e6-c8a53090103f 10/2/24, 11 35 AM Page 4 of 8 :  form arginosuccinate Arginosuccinate Lyase: breaks down arginosuccinate to form arginine and fumarate Arginase “Arginase takes arginine and breaks it down to form urea.” Deficiencies in the Urea Cycle Enzyme Deficiency Effect Argininosuccinate Synthetase High concentrations of citrulline Arginase Low concentrations of ornithine Activation of the Urea Cycle The urea cycle is activated by the flow of nitrogen. N-Acetylglutamate Synthetase: generates N-Acetylglutamate, which activates CPS 1. Urea Precursors Aspartate: a urea precursor Free Ammonium Ion: a urea precursor Carbamyl Phosphate: a urea precursor Hyperammonemia Story https://www.turbolearn.ai/content/a18feabb-9819-4296-a5e6-c8a53090103f 10/2/24, 11 35 AM Page 5 of 8 :  We will discuss the hyperammonemia story with regards to two enzymes: Ornithine Transcarbamylase and Carbonyl Phosphate Synthetase 1.## Hyperammonemia Definition: Hyperammonemia is a condition characterized by elevated levels of ammonia (NH₃) in the blood. Urea Cycle The urea cycle is a series of chemical reactions that occur in the liver and kidneys to detoxify ammonia. The cycle consists of the following enzymes: Carbamylphosphate synthetase 1 (CPS 1) Ornithine transcarbamylase (OTC) Argininosuccinate synthetase Argininosuccinate lyase Arginase The urea cycle starts with the production of carbamylphosphate from ammonia and bicarbonate, catalyzed by CPS 1. The carbamylphosphate then reacts with ornithine to form citrulline, which is converted to argininosuccinate, and eventually to urea. Clinical Signs and Symptoms Elevated ammonia levels Decreased BUN (Blood Urea Nitrogen) Increased blood glutamine levels https://www.turbolearn.ai/content/a18feabb-9819-4296-a5e6-c8a53090103f 10/2/24, 11 35 AM Page 6 of 8 :  Central edema, lethargy, convulsions, coma, and death Enzyme Deficiencies Ornithine Transcarbamylase (OTC) Deficiency Elevated carbamylphosphate levels in the mitochondria Carbamylphosphate can cross the inner mitochondrial membrane and enter the cytosol Artificial stimulation of pyrimidine biosynthesis, resulting in increased orotic acid production Diagnosis: Elevated ammonia levels, decreased BUN, and elevated orotic acid levels Carbamylphosphate Synthetase 1 (CPS 1) Deficiency Decreased carbamylphosphate levels No artificial stimulation of pyrimidine biosynthesis Diagnosis: Elevated ammonia levels, decreased BUN, and no orotic acid Pyrimidine Biosynthesis Definition: Pyrimidine biosynthesis is the process of producing pyrimidine nucleotides, which are essential for DNA and RNA synthesis. Carbamylphosphate is used in pyrimidine biosynthesis https://www.turbolearn.ai/content/a18feabb-9819-4296-a5e6-c8a53090103f 10/2/24, 11 35 AM Page 7 of 8 :  Orotic acid is an intermediate compound in the pyrimidine biosynthesis pathway Deficiencies in pyrimidine biosynthesis can also result in elevated orotic acid levels, making it essential to differentiate between OTC deficiency and pyrimidine biosynthesis deficiency. Differential Diagnosis Ammonia Orotic Acid Condition Levels BUN Levels OTC Deficiency Elevated Decreased Elevated CPS 1 Deficiency Elevated Decreased None Pyrimidine Biosynthesis Normal Normal Elevated Deficiency https://www.turbolearn.ai/content/a18feabb-9819-4296-a5e6-c8a53090103f 10/2/24, 11 35 AM Page 8 of 8 :