Amino Acids, Proteins and Porphyrins
Urea cycle occurs in? (AIPG 2011)
Urea cycle occurs in Liver.
- Urea is synthesized in Liver and cleared by kidney.
- Urea is the major end product of N2 catabolism of human.
- Although brain tissues can form urea, but major mechanism for detoxification of NH3 is glutamine formation.
- The urea cycle occurs exclusively in liver.Q
- Kidney: urea cycle operates in limited extend: Kidney can form up to ariginine but cannot form urea as enzyme Arginase is absent in kidney.Q
- Brain can synthesize urea from citrulline but lacks enzymes for forming citrulline from ornithine.
- Synthesis of 1mole of urea requires 3 mol of ATP and 1 mol each of ammonium ion (NH4+) and the α-amino nitrogen of Asparate.
- N-Acetyl glutamate functions solely as an enzyme activator. i.e. Allosteric activator of carbamoylphosphate synthase I.
- In mammals, the major role of ornithine, citrulline and arginino-succinate, is urea synthesis.
- Carbomoyl phosphate synthase-I is rate limiting or Pace maker enzyme of the urea cycle. It is a hepatic mitochondrial enzyme.
- Carbomoyl phosphate synthase-II a cytosolic enzyme that uses glutamine rather than NH3 as the nitrogen donor, functions in pyrimidine biosynthesis.
- Arginase release urea and L-ornithine from L-Arginine.
- L-glutamate is the only amino acid that under goes oxidative deamination.
- Major reaction involved in Ammonia production in kidney that secreted into urine: -
a. Glutaminete Glutamate + NH+
b. Glutamate a-Ketoglutarate + NH+
(Note – NH4 NH3 + H+, in urine)
c. The principal reaction producing NH4 + in cell is conversion of glutamine to glutamate by Glutaminase.
1. Arginase: - Produces urea from L-Arginine in urea cycle in Liver.
2. Urease: - An enzyme that accelerates the hydrolysis of urea into the CO2 and NH3. it is used in determining the amount of urea in blood or in urine.
4th step in urea cycle:
Disorders of Urea cycle
a. All metabolic defects of urea cycle, whether due to accumulation of ammonia (I and II stages), citrulline (Ill stage), argininosuccinic acid or arginine (IV tages) are toxic for the brain. These patients are intolerant to protein food and show a dislike for these.
b. Recurrrent vomiting and irritability are observed early in Iife. The disease progresses rapidly to lethargy, coma, and convulsions. Clinical features include mental ion, muscular rigidity, opisthotonos and delayed development.
c. Patients of argininosuccinic academia have dry, breakable, and short hair. Blood urea levels are nearly thus indicating that the metabolic blocks are not complete.
a. Hyperammonemic states (organic acidias, urea cycle defects) - appropriate dietary ion of proteins (in acute stage 0.25 g/kg/d as a mixture of essential amino acids and later 1-1.5 g/kg/day). Low Protein diets are also available commercially.
b. Sodium benzoate (250-500 mg/kg/day in 4-6 divided doses orally) administered as it conjugates with NH3 and forms nontoxic metabolite that is easily excreted. Sodium acetate (250-500 mg/kg/day) and arginine (200ng/kg/day) are also effective.
c. Carnitinesuplimentation has also been recommended with acetate and benzoate. Catabolic states triggering ammonemia should be avoided. Gene therapy is under investigation.
d. Hemodialysis or hemofiltration should be instituted if ammonia exceeds 500 Ilmol/L.. Sustained ammonia greater than 800 mmol/L for >24 h are associated reversible neurological damage.