Urea cycle disorder
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The document provides an in-depth overview of urea metabolism, detailing the processes of amino acid breakdown, urea cycle function, and associated metabolic disorders known as urea cycle disorders (UCDs). It discusses various UCDs, their genetic basis, clinical features, and treatment options. The document emphasizes the significance of ammonia in metabolism and the potential consequences of its accumulation in the body.
Urea cycle disorder
- 1. Mohammad Reza Abdullahi Master of Medical Science student in Biochemistry International Islamic University Malaysia
- 2. Urea is end product of protein metabolism After a meal that contains protein, amino acids released by digestion Pass from the gut through the hepatic vein to the liver AA are used for the synthesis of protein Excess AA may be converted to glucose or TG Amino group of AA converted to urea in the liver 2
- 3. Purine metabolism Transdeamination of glutamate Deamination Bacterial action in the gut 3
- 4. The binding of ammonia in the synthesis of glutamate causes an outflow of α- ketoglutarate from the tricarboxylic acid cycle, with decreased formation of ATP energy and deteriorates the activity of cells The producing ammonia transform glutamic acid - glutamine - an osmotically active substance. This leads to water retention in the cells and the swelling that causes swelling of tissues. In the case of nervous tissue it can cause brain swelling, coma and death The use of α-ketoglutarate and glutamate to neutralize the ammonia causes a decrease in the synthesis of γ-aminobutyric acid (GABA) inhibitory neurotransmitter of the nervous system 4
- 5. Glutamine transport ammonia in the blood stream Alanine transport ammonia from skeletal muscle to liver via glucose-alanine cycle 5
- 6. Urea cycle described by Krebs and Henseleit in 1932 This cycle is the primary pathway to dispose of nitrogenous waste in mammals It involves five catalytic enzymes, a cofactor-synthesizing enzyme, and at least two transport proteins that are involved in the facilitation of nitrogen transfer between subcellular compartments One nitrogen of urea molecule is supplied by free ammonia and the another nitrogen by aspartate The carbon and oxygen of urea are derived from CO2 Urea is produced by the liver and then is transported in the blood to the kidneys for excretion in the urine 6
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- 8. UCDs are inborn errors of metabolism characterized by the inability to efficiently dispose of waste nitrogen It result in hyperammonemia, encephalopathy and respiratory alkalosis There are 5 major type of UCDs Ornithine transcarbamoylase deficiency Carbamoyl phosphate synthetase deficiency Argininosuccinate synthetase deficiency or citrullinemia Argininosuccinate lyase deficiency Arginase deficiency UCDs frequency in japan is 1 in 46000 8
- 9. Autosomal recessive disorder CPS 1 catalyze formation of carbamoyl phosphate from ammonium and bicarbonate Causes hyperammonemia 9
- 10. COOH NH NH2 NH C NH2 COOH CH2 CH2 CH2 CH H2ONH2 NH2 OC CH2NH2 CH2 COOH H COOH CH2 COOH CH CH2 NH2 O NH2 NH C NH2 COOH CH2 CH2 CH2 CH CH2N ATP NH NH C NH2 COOH CH2 CH2 CH2 CH NH CH COOH COOH CH2 HC COOH CH O NH2 CH2NH2 COOH NH2 NH CH2 C CH2 NH2 C COOH CH2 CH2 H CH2 CH O- O- O POC O CO2 + NH4 H2N 2 ATP Mitochondrion + ADP + Pi carbamoyl phosphate synthetase I (CPSI) 1 Carbamoyl phosphate Ornithine ornithine transcarbamoylase Pi Citrulline 2 Ornithine Citrulline Aspartate AMP + PPi Argininosuccinate Fumarate Arginine 3 4 5 argininosuccinate synthetase argininosuccinase Urine Cytosol urea NH4+ + Glu Gln Carbamoyl P orotic acid 10
- 11. It has two form Early onset form characterized by moderate to sever cerebral damage and hyperammonemic coma in neonatal CPS enzyme is totally absent Delayed onset form Due to the partial deficiency of CPS enzyme Intermediate seizure may be present with episode of vomiting, mild abdominal pain and muscle weakness 11
- 12. Intravenous administration of sodium benzoate IV administration of phenyl acetate 12
- 13. X-linked inborn error of metabolism of the urea cycle It catalyze transfer of carbamoyl from CP to ornithine Causes hyperammonemia, encephalopathy and respiratory alkalosis It characterized by high orotic acid level following high protein diet OTC deficiency has a frequency of 1 in 80000 birth in Japan 13
- 14. Chronic ammonia intoxication and mental retardation are the major features It has two form Milder form Activity of enzyme is upto 25% Sever form Activity of enzyme is 5-7% Skin lesions Treatment: administration of sodium benzoate 14
- 15. COOH NH NH2 NH C NH2 COOH CH2 CH2 CH2 CH H2ONH2 NH2 OC CH2NH2 CH2 COOH H COOH CH2 COOH CH CH2 NH2 O NH2 NH C NH2 COOH CH2 CH2 CH2 CH CH2N ATP NH NH C NH2 COOH CH2 CH2 CH2 CH NH CH COOH COOH CH2 HC COOH CH O NH2 CH2NH2 COOH NH2 NH CH2 C CH2 NH2 C COOH CH2 CH2 H CH2 CH O- O- O POC O CO2 + NH4 H2N 2 ATP Mitochondrion + ADP + Pi carbamoyl phosphate synthetase I (CPSI) 1 Carbamoyl phosphate Ornithine ornithine transcarbamoylase Pi Citrulline 2 Ornithine Citrulline Aspartate AMP + PPi Argininosuccinate Fumarate Arginine 3 4 5 argininosuccinate synthetase argininosuccinase Urine Cytosol ureaNH4+ + Glu Gln Carbamoyl P orotic acid 15
- 16. NAGS catalyze formation of NAG from glutamine and acetyl CoA N-acetyl glutamate is an activator of CPS 1 NAGS deficiency causes high concentration of ammonia and glutamine 16
- 17. Patients have vomiting, uncontrollable movement, developmental delay, visual impairment…. It characterized by hyperammonemia without increased excretion of orotic acid Treatment: administration of carbamoyl glutamate which activates CPS 1 17
- 18. Called argininosuccinase defeciency, argininosuccinate lyase deficiency Autosomal recessive disorder Argininosuccinase cleave argininosuccinate to yield arginine and fumarate It characterized by low arginine as well as hyperammonemia 18
- 19. Clinical features include mental and physical retardation, convulsion, episodic unconsciousness, liver enlargement and skin lesions It has two type, early onset type which is fatal and late onset type Treatment : arginine supplemented diet as well as low protein diet 19
- 20. Also called citrullinuria and argininosuccinate synthetase deficiency Argininosuccinate synthetase combines citrulline with aspartate to form argininosuccinate It is characterized by orotic acid urea and hyperammonemia Clinical features are sever vomiting which begin at the age of 9 months and mental retardation Symptoms included delayed menarche, insomnia, nocturnal sweats, recurrent vomiting, tremors, lethargy, convulsions and hallucination 20
- 21. It has 3 type Type 1 which is duo to the changes in the kinetic properties of enzyme Type 2 or late onset form Type 3 which is characterized by no detectable enzyme activity and no translation activity for ASS mRNA Treatment: with the early use of sodium benzoate and phenyl acetate to remove nitrogen by alternative pathway 21
- 22. Also called Arginase deficiency and hyperargininemia Autosomal recessive disorder Arginase hydrolyzes arginine to ornithine and urea and is virtually exclusive to the liver The patients present with psychomotor retardation, epileptic seizures and spastic paraplegia Children may have vomiting, hypotonia, irritability and ataxia Arginase deficiency dose not commonly have the sever hyperammonemia Treatment: administration of sodium benzoate and dietary restriction of arginine 22
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- 24. Liberman, M & Marks, Allan. (2013). MARKS’ Basic Medical Biochemistry (a clinical approach) (fourth edition). Lippincott Williams & Wilkins, a Wolters Kluwer business Chawla, R. (2010). Clinical chemistry (Organ function Tests, Laboratory Investigations and Inborn Metabolic Disease) (second edition). Jaypee Brothers Medical Publishers. Lee, B., & Scaglia, F. (2015). Inborn Error Of Metabolism. oxford university press. 24
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Editor's Notes
- #4: The combined action of an aminotransferase and glutamate dehydrogenase is referred to as transdeamination.
- #6: In many tissues, including the brain, some processes such as nucleotide degradation generate free ammonia. Glutamine is non toxic compound that can transport ammonia into the blood or liver and kidney.
- #7: N acetylglutamate as cofactor. The transport of ornithine into the mitochondria and citrulline into the cytosol across the semipermeable mitochondrial membrane is facilitated by ornithine transporters type 1, 2, 3 (ORNT1, ORNT2, and ORNT3; also known as SLC25A15, SLC25A2, and SLC25A29, respectively) through the ornithine/citrulline proton antiport mechanism.
- #13: Phenylacetate has a bad odor, which makes it difficult to take orally.) As indicated in Figure 38.18A, benzoic acid, after activation, reacts with glycine to form hippuric acid, which is excreted. As glycine is synthesized from serine, the body now uses nitrogens to synthesize serine, so more glycine can be produced. Phenylacetate (see Fig. 38.18B) forms a conjugate with glutamine, which is excreted. This conjugate removes two nitrogens per molecule and requires the body to resynthesize glutamine from glucose, thereby using another two nitrogen molecules.
- #14: When ornithine transcarbamoylase (OTC) is deficient, the carbamoyl phosphate that normally would enter the urea cycle accumulates and floods the pathway for pyrimidine biosynthesis. Under these conditions, excess orotic acid (orotate), an intermediate in pyrimidine biosynthesis, is excreted in the urine. It produces no ill effects but is indicative of a problem in the urea cycle.
- #20: ASA contains 2 waste nitrogen atoms later excreted in urine in healthy persons, and it has a renal clearance similar to urea. Hyperammonemia might be relieved by arginine therapy
- #23: Hyperammonemia seen with arginase deficiency is less severe because arginine contains two waste nitrogens and can be excreted in the urine