Urea cycle
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1) Ammonia is produced in tissues and transported to the liver where it is detoxified to urea in the urea cycle. The three main transport forms are glutamate, glutamine, and alanine. 2) The urea cycle converts ammonia and carbon dioxide to urea using enzymes in the liver mitochondria and cytoplasm. This prevents ammonia toxicity. 3) Genetic defects in urea cycle enzymes can cause hyperammonemia, leading to complications like cerebral edema, seizures, coma and death if not treated. Treatment aims to reduce ammonia levels and promote its excretion through alternate pathways.
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Urea cycle
- 1. Dr. N. Sivaranjani Asst. Prof. 1 BY VANA JAGAN MOHAN RAO M.S.Pharm, MED.CHEM NIPER,KOLKATA Asst. Professor, MIPER- KURNOOL Email: jaganvana6@gmail.com
- 2. * Ammonia is produced in most tissues – less than 1% is TOXIC especially to CNS Readily ionizes to ammonium ion NH4 + *It is immediately removed from the circulation and detoxified to Urea in the LIVER. * Three transport forms of NH3 from peripheral tissues to LIVER: 1. Glutamate – ALL tissues 2. Glutamine – Brain 3. Alanine - Muscle 4NH + pKa = 9.3 NH3 + H+ 2
- 3. 3NH +CH COO- COO- CH2 CH2 Glutamate NH3 +CH CO-- CH2 CH2 Glutamine 3NH +CH COO- COO- CH2 CH2 Glutamate ATP ADP+Pi NH3 NH3 H2O Glutamine synthetase COO- Glutaminase Liver Mitochondria NH2 Glutamine is a non-toxic carrier of ammonia from Brain . It is released into blood circulation and carried to liver. Urea cycle Brain 3
- 4. Glucose-Alanine cycle 4 • Glucose Alanine Cycle / Cahill Cycle Plays a dual role : • Transports ammonia from muscle to liver in a non-toxic form (Alanine) • Transports carbon skeleton to liver for gluconeogenesis Alanine is safe way to transport ammonia from muscle to liver via blood.
- 5. Amino acids G L U T A M A T E NH3 α Keto glutarate Glutamate dehydrogenase Transamination Glutamine Glutamate Glutamate NH3 Urea Glutamine synthetase Glutaminase Alanine Brain Liver Aspargine Muscle All cells Pyruvate NH3 Aspartate Aspartate Liver Liver 5
- 6. Sources of Ammonia 6 Intestine GLUTAMINE Glutamate Bacterial degradation of Urea GDH GLUTAMATE Serine Threonine Histidine Pyruvate α KB Urocanate NH4 + Purine Pyrimidine Catabolism ASPARGINE Aspartate Oxidation of Monoamine by MAO Amino Sugars Non Oxidative Deamination Oxidative Deamination
- 7. Biochemical basis of Ammonia toxicity 7 • In Brain cell Mitochondria – excess NH3 reacts with αKG to form GLUTAMATE by GDH – dec. αKG – dec. TCA cycle- dec. Glucose utilization & ATP generation. not universally accepted. Glutamate depletion – NH3 Inhibits glutaminase – depletes glutamate which is a excitatory NT. Glutamine is accumulated in neurons – osmotic shift of H2O into the cell- Edema & swelling of Astrocytes.
- 8. Neuronal dysfunction – inc. permeability of K+ & Cl- ions Accumulation of Excito- toxins – inc. transport of Tryptophan across BBB – its Metabolites are accumulated – which are Excito-toxins. 8
- 9. Excretory forms of Nitrogen 9 Mammals including human beings The basic features of nitrogen metabolism were elucidated initially in pigeons
- 10. Urea cycle 10 Krebs–Henseleit urea cycle / Ornithine cycle Site – LIVER Subcellular organelle – Mitochondria , cytoplasm – 2 steps occur in mitochondria, remaining in the cytosol. Converts NH3 into harmless Urea
- 11. • Disposable form of NH3 • Accounts for 90% of NPN in Urine UREA • 1 N – Ammonia • 2 N – Aspartate • C & O – CO2 11
- 12. H3N-CO-O-PO3 NH3 + CO2 + H2O 2 ATP 2 ADP + Pi Carbamoyl Phosphate Citrulline Argininosuccinate Ornithine Aspartate UREA H2O Argininosuccinate lyase Arginase H2N-CO-NH2 Transporter Carbamoyl PO4 synthetase I Ornithine Trans Carbamoylase Argininosuccinate synthetase 12 Cytosol
- 13. Significance Of Urea Cycle 13 2 N of urea ( H2N-CO-NH2) – NH3 , amino N of Aspartate Disposes 2 waste products – NH3, HCO3 - Arginase E – only in LIVER Forms SEAA – Arginine Ornithine is regenerated – Polyamine syn. , NEAA syn. - proline Fumarate is the link b/w UREA & TCA cycle – Kreb’s bi cycle
- 14. Relationship b/w Urea cycle & TCA cycle 16
- 15. Difference b/w CPS I and CPS II 15 CPS -I CPS-II Location Mitochondria Cytosol Nitrogen donor NH3 Glutamine Participates Urea Cycle Pyrimidine Biosynthesis Regulated Activated – NAG (N-Acetyl glutamate) Inhibited - CTP
- 16. Over all reaction 16 NH3 + CO2 + Aspartate + 3 ATP UREA
- 17. Energetics of Urea Cycle 2 ATP • Reaction 1 2 ATP • Reaction 3 TCA cycle 17 Via Fumarate Malate – OAA 1 NADH=3ATP 4 ATP (UREA CYCLE) – 3 ATP (TCA CYCLE) = 1 ATP
- 18. Regulation 18 • Feed forward mechanism / Coarse regulation – regulated by substrate availability High PROTEIN diet – induces CPS-I Prolonged starvation – inc. Catabolism of proteins - induces GDH- inc. NH3 – urea cycle. * Allosteric mechanism – CPS -I stimulated by N-Acetyl Glutamate (NAG)
- 19. Allosteric Mechanism 19 Acetyl - CoA+ Arginine, Prolonged Starvation + High protein diet, Glutamate , Glutamate Acetyl Glutamate synthase N-Acetyl Glutamate CPS – I of Urea Cycle +
- 20. 20 Fate of UREA
- 21. Disorders of UREA cycle 21 • Genetic defect have been described in all enzymes of urea cycle - results in ammonia intoxication • These are extremely rare – 1 in 30,000 live births • Autosomal Recessive , except OTC defect – X linked • Defect in reaction 1 and 2 – accumulation of Ammonia directly • Defect of later enzymes - accumulation of intermediates
- 22. Common features seen are – severity varies Feeding difficulties , Lethargy , irritability , protein induced vomiting and poor intellectual development – MR ,cerebral edema, seizures leads to COMA and death 22
- 23. Disorders Defective Enzyme Products Accumulated Clinical features 23 Hyperammonaemia CPS – I Ammonia Severe hyperammonemia type – I Mental retardation , developmental delay Variant of N acetyl Ammonia Neonatal Hyperammonemia – hyperammonemia glutamate Fatal. type I synthase Rx -N-carbamoyl-L-glutamate – activates CPS-I Hyperammonaemia OTC , X- Ammonia Orotic aciduria -channeling of type – II linked CP to Pyrimidine syn.
- 24. Hepatic Coma (Acquired Hyperammonemia) Portal systemic Encephalopathy • / Hepatic encephalopathy Hepatic failure –finally lead to hepatic coma and death Hyperammonemia – characteristic feature of liver failure C/F - Altered sensorium, convulsions, ascites, jaundice, hepatomegaly, cerebral edema, hemorrhage. 24 Urea
- 25. 25
- 26. 26 • Dietary restriction of protein – Mainstay of management Replacement of EAA by their corresponding α-Keto acids – dec. N disposal – without causing EAA deficiencies. • Maximal calories should be provided in the form of I.V glucose & lipids to reduce catabolism. •Promote N excretion in forms other than Urea Block due to Argininosuccinate lyase defect – supplement Arginine diet – Argininosuccinate is excreted. First 2 blocks – supplement diet with Benzoate & Phenylacetate Treatment
- 27. Treatment for first 2 defects Benzyl CoA + Glycine = Hippuric acid Phenylacetyl CoA + Glutamine = Phenylaceylglutamine Arginine Urea Citrulline Argininosuccinate Aspartate Ornithine Arginine supplements Excreted in URINE 27
- 28. Treatment 28 • Gene therapy is in experimental stage • Neonatal Hyperammonaemia – Medical emergency - requires rapid lowering of NH3 - Hemodilaysis , - Exchange Transfusion , - Peritoneal dialysis • Hepatic Encepahalopathy - sterilization of Gut – Lactulose laxative - liver transplantation - Treat the underlying cause.