Urea Cycle and Ammonia Metabolism PDF

# Urea Cycle and Ammonia Metabolism ## Introduction * **N.B.** * 1st $NH_2$ comes from L-glutamic Acid by L-glutamate Dehydrogenase. * 2nd $NH_2$ comes from the amino group of Aspartate. * Ornithine and Citrulline are amino acids in the Urea Cycle but not in tissue proteins (They have...

# Urea Cycle and Ammonia Metabolism ## Introduction * **N.B.** * 1st $NH_2$ comes from L-glutamic Acid by L-glutamate Dehydrogenase. * 2nd $NH_2$ comes from the amino group of Aspartate. * Ornithine and Citrulline are amino acids in the Urea Cycle but not in tissue proteins (They have no codons on DNA). ### Short Term Regulation of Urea cycle: 1. Carbamoyl Phosphate Synthetase I (rate limiting Enzyme). * Active only in the presence of N-Acetyl glutamate (Allosteric activator). 2. Excess $NH_3$ → stimulate Urea formation. 3. High Urea level inhibit CPS I (reaction 1), Ornithine Trans carbamoylase (reaction 2) and Arginase (reaction 5). 4. Arginine activates N-acetyl Glutamate synthase (Cytosol) → ↑↑↑ N-Acetyl glutamate → ↑↑↑ Urea. **N-Acetyl Glutamate** **N-Acetyl Glutamate Hydrolase** **Acetate + Glutamate** ### Long Term Regulation of Urea cvcle: 1. Protein Free diet decreases enzymes Level. 2. Increase dietary protein or Starvation increase enzymes Level. ### Glutamate importance in Urea cycle: 1. Forms N-Acetyl Glutamate (Activator of CPS-I) 2. By L-Glutamate Dehydrogenase gives $NH_3$. 3. Glutamate & Oxaloacetate transamination → Aspartate. ### Urea Fate: 1. Liver Urea → Blood (10-50 mg/dL) → Kidney Excreted in Urine. 2. Little Urea is excreted in sweat and bile. 3. Bile Urea → Bacterial Urease in intestine → $CO_2$ + $NH_3$. 4. Part of $NH_3$ is lost in feces & part is reabsorbed to liver to re-form Urea. | Organ | CPS I | CPS II | |---|---|---| | Site | Liver only | Widely distributed | | Source of N | Mitochondria | Cytoplasm | | Pathway | Ammonia | Amine group of Glutamine | | Regulation | Urea Synthesis | Pyrimidine Synthesis | | | Controlled by N-Acetyl Glutamate | Not controlled by it | ## B. Urea: * The most important disposal form of Ammonia. * It is the major End product of Nitrogen (Protein) catabolism representing 90% of nitrogen Excreted. ### Kerbs Urea Cycle (Krebs Hensleit Cycle) * Urea is formed in Liver from 1 $CO_2$ + 2 $NH_3$ using 3 ATPs + Break 4 high energy bonds. * Urea is the only product in this cycle. Other intermediates are regenerated. * First 2 reactions → Mitochondria * Rest 3 reactions → Cytoplasmic  ### Link between Krebs Urea Cycle & Krebs T.C.A (C.A.C): 1. Fumarate is hydrated to Malate which is either: * Oxidized in C.A.C in mitochondria → Energy. * Oxidized in Cytosol to Oxaloacetate which is either: * Transaminated to Aspartate → Re-enter Urea Cycle. * Used in Glucose synthesis (by Gluconeogenesis GNG). 2. $CO_2$ used in Urea cycle comes from T.C.A. ## B. Catabolic and Excretory pathways:- * **In the Liver:** 1. Majority of $NH_3$ (90%) produce Urea in Liver by Urea cycle → Blood → Kidney → Urine. 2. Glutamine synthesis especially in Acidosis. * **In the Kidney:** 1. Excretion in Urine (40% of Urinary Ammonia). * **In Extra-renal tissues:** 1. Converted to Glutamine especially in Brain. 2. Glutamine → Blood → kidney → Renal Glutaminase → Glutamic Acid + Ammonia (60% of Urinary Ammonia). ### Ammonia Transport in Circulation * Ammonia level in blood is very low due to: * Rapid removal of Ammonia from blood by Liver. * Many tissues as muscles release nitrogen as Glutamine and Alanine. * Ammonia is transported in circulation as Urea and Glutamine (Non-Toxic forms of Ammonia). ## A. Glutamine: * Amide of Glutamic Acid → Non-toxic storage and transport of $NH_3$. * Glutamine formation occurs in Muscle and Liver. * Major Mechanism of Ammonia removal from Brain. * Its blood level is higher than other amino acids (Transport Function). * Removed by Renal Glutaminase (Deaminated).  ## b) Non-oxidative (Direct or Specific) Deamination: * Serine → Serine Dehydratase (PLP) → Pyruvate + $NH_3$. * Threonine → Threonine Dehydratase (PLP) → a-Keto Butyrate + $NH_3$. * Glycine → Glycine Cleavage System→ $CO_2$ + $NH_3$. * Glycine → Glycine Oxidase → Glyoxylic Acid + $NH_3$. * Cysteine → Cysteine Desulfhydrase → Pyruvate + $NH_3$. * Homoserine → Homoserine Deaminase → a-Keto Glutarate + $NH_3$. * Histidine → Histidase → Urocanic Acid + $NH_3$. ### Hydrolytic Deamination: * Glutamine → Glutaminase → Glutamate + $NH_3$. * Asparagine → Asparaginase → Aspartate + $NH_3$. ### Reductive Deamination: * Amino acids → large intestine Bacteria (Putrefaction) → Organic acids. ## Metabolism of Ammonia  ## Fates of Ammonia (Removal of Ammonia): ### A. Anabolic:- 1. Amination of a- keto acid to from non-essential amino acids. 2. Synthesis of Purines, Pyrimidines and Amino Sugars. ## B. Minor Deamination: ### a) Oxidative Deamination by Amino acid oxidases: * Occur in Liver and Kidney. * It Includes Removal of Hydrogen (Oxidation) and $NH_3$ (Deamination). #### D-Amino Acid Oxidase * D-Amino Acid * Plants & Cell wall of Microorganism * FAD → FADH₂ * a- keto Acid + $NH_3$ #### L-Amino Acid Oxidase * L-Amino Acid * a- keto Acid + $NH_3$ * FMN → FMNH₂ * FAD has limited natural occurrence in mammals & high activity. * FMN has high natural occurrence and low activity.