excretion and urea cycle regulation of urea cycle Nitrogen excretion Nitrogen excretion means elimination of nitrogen containing compounds from an organism Urine is the main rout for such excretion also take place through feces ID: 1015854
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1. BIOCHEMISTRY Topic : nitrogen excretion and urea cycle; regulation of urea cycle;
2. Nitrogen excretion:Nitrogen excretion means elimination of nitrogen containing compounds from an organism.Urine is the main rout for such excretion, also take place through feces.End products: Ammonia Uric acid Urea All these end products contain nitrogen.
3. Uric Acid:Insoluble compound which is a breakdown product of nitrogenous metabolism.Heterocyclic compound of C, H, O, N.Molecular formula is C5H4N4O3.Animals that excrete most of their waste nitrogen in the form of uric acid, usually in the urine, are called Uricotelic. Such as birds, reptiles and insects.
4. Uric acid metabolism:Uric acid production and metabolism are complex processes.Uric acid is the end product of; 1 : Exogenous purine metabolism 2 : Endogenous purine metabolismExogenous production of uric acid is from diet and endogenous production of uric acid is mainly from liver, intestine, kidneys and vascular endothelium.
5. Purine nucleotide degradation:Dietary DNA and RNA are degraded in the small intestine lumen to give free purine bases.Purine bases are transported to intestinal mucosal cells.Inside intestinal mucosal cells, purine bases are catabolized into Uric acid.Uric acid is transported to blood and finally in the kidney to appear in urine.
6. Enzymes involvement: Many enzymes are involved in the conversion of two purine nucleic acid, Adenosine and Guanine, to Uric acid. Major enzymes are:NucleotidaseAdenosine deaminaseXanthine oxidaseNucleotidase:Adenosine monophosphate(AMP) is converted to inosine via two different mechanism; either - first removing amino group by deaminase to form inosine monophosphate(IMP) Followed by dephosphorylation, - or first removing phosphate group by nucleotidase to form adenosine.Guanine monophosphate(GMP) is converted to guanosine by nucleotidase, which further converted to guanine and then to uric acid by guanine deaminase.
7. Adenosine deaminase:Adenosine deaminase (ADA) is an important enzyme in the purine metabolism that catalyzes the deamination of adenosine to inosine.Adenosine plays an important role in different metabolic and pathological conditions, such as the intrarenal metabolic regulation of kidney function, in asthma and hypoxia, in cardiac ischemia, and in regulating the severity of inflammation during an immune response.Adenosine is also associated with Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, epilepsy, drug addiction, and sleep.Xanthine oxidase:The physiological role of xanthine oxidoreductase enzyme (XOR) is to catalyze the terminal two reactions of purine catabolism in human.In particular XOR catalyses the oxidation from hypoxanthine to xanthine and from xanthine to uric acid, with the simultaneous reduction of NAD+ or O2.This enzyme exists in two forms: - xanthine dehydrogenase (XDH), which prefers NAD+ as electrons acceptor. - xanthine oxidase (XO), which prefers O2. When the oxygen is the final electron acceptor electrons bind unstably to oxygen forming hydrogenperoxide (H2O2) and superoxide anion (O•−).
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9. In the left panel for XDH, xanthine is oxidized to uric acid and electrons transferred via Fe/Scenters to the FAD where NAD+ is reduced to NADH. In the right panel for XO, xanthine is oxidized to uric acid and electrons are transferred to the FAD where O2 is reduced to O•−and H2O2.
10. Hyperuricemia:Hyperuricemia is a key risk factor for the development of gout, renal dysfunction, hypertension, hyperlipidemia, diabetes and obesity.Causes: Hyperuricemia occurs as a result of the increased uric acid production, the impaired renal uric acid excretion, or a combination of the two. It is characterized by high uric acid level in the blood, causing deposition of urate crystals in the joints and kidneys. Generally, hyperuricemia in adults is defined as a blood uric acid concentration greater than 7.0 mg/dL in men and 6.0 mg/dL in women. In normal humans, uric acid is excreted in urine. However, uric acid excretion may be impaired by kidney disease, leading to hyperuricemia.XOR represents the most relevant pathway involved in uric acid overproduction and offers significant perspectives for a better pharmacological approach for treating hyperuricemia-related vascular and non vascular disorders.
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12. Urea cycleDefine:Ammonia is a toxic, and even small amount will damage the nervous system.In humans and most other terrestrial mammals, urea is a major nitrogen excretion product.Most urea is produced in liver.Excretion of urea is, however associated with a considerable loss of water due to osmotic pressure.
13. Urea cycleThe urea cycle is smaller than the TCA cycle.Carbamoyl phosphate synthetase I is the mitochondrial enzyme that catalyzes the formation of carbamoyl phosphate from inorganic ammonium and carbonate.The usual fate of the ammonium fixed by the carbamoyl phosphate synthetase I is excretion in the form of urea and therefore this enzyme is
14. Urea cycleUsually considered separately from glutamine synthetase and glutamate dehydrogenase, which fix ammonium for use in metabolism.Ornithine transcarbamoylase to produce citrulline.Citrulline then leaves the mitochondria using a specifictransporter, because the remaining reactions occur in the cytoplasm. Once in thecytoplasm, citrulline is combined with aspartate by argininosuccinatesynthetase to form argininosuccinate, in a reaction that requires ATP, and produces AMP and pyrophosphate.
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16. Urea cycleThe arginine contains nitrogens derived fromornithine, from the free ammonium, and from the aspartate. Arginine is thencleaved by arginase to release urea and to regenerate ornithine.the urea cycle is controlled by two factors: regulatedenzymes and substrate availability. For the urea cycle the regulated enzyme iscarbamoyl phosphate synthetase I. For the urea cycle, the availability of cycleintermediates and free ammonium also control the cycle.
17. Urea cycleOrnithineOrnithine is the equivalent of the TCA cycle intermediate oxaloacetate; levels of ornithine tend to control the rate of the urea cycle. Ornithine can be produced in several ways. One method of increasing ornithine levels is to take up arginine from a source outside the cell (either from protein breakdown or from a dietary source).A second method is to synthesize ornithine directly. Ornithine synthesis normallybegins with glutamate, although proline can also act as a source of ornithine synthesis.
18. Urea cycleRegulation of ammonium metabolismIn humans, the most important reaction for releasing ammonium from amino acidsis catalyzed by glutamate dehydrogenase.The major enzyme used for incorporating free ammoniuminto organic compounds, glutamine synthetase is also regulated. Glutaminesynthetase activity is stimulated by a-ketoglutarate.
19. Ammonia toxicityAmmonia encephalopathy Increased concentration of ammonia in the blood and other biological fluids → ammonia difuses into cells, across blood/brain barrier → increased synthesis of glutamate from a-ketoglutarate, increased synthesis of glutaminea-ketoglutarate is depleted from CNS → inhibition of TCA cycle and production of ATPNeurotransmitters – glutamate (excitatory neurotr.) and GABA (inhibitory neurotr.), may contribute to the CNS effects – bizarre behaviour
20. Enzyme deficiencyIf symptoms are not detected early enough → severe mental retardation → brain damage is irreversible.N-acetylglutamate synthase deficiency:Hyperammonemia and general hyperaminoacidemia in a newborn (liver contain no detectable ability to synthesize N-acetylglutamate).Early symptoms include lethargy, vomiting, and deep coma.
21. Enzyme deficiencyCarbamoyl phosphate synthetase (CPS I) deficiency:autosomal recessive metabolic disorder, associated with mental retardation and developmental delay.Hyperammonemia has been observed in 0 – 50% of normal level of CPS-I synthesis in the liver.Ornithine transcarbamoylase (OTC) deficiencyThe most common urea cycle disorder, resulting in a mutated and ineffective form of the enzyme.X-linked recessive disorder caused by a number of different mutations in the OTC gene – males are generally more seriously affected than females (males are asymptomatic as heterozygotes).Complications with OTC may include mental retardation and developmental delay.
22. Enzyme deficiencyArgininosuccinate lyase deficiency (argininosuccinate aciduria)Rare autosomal recessive disorder, argininosuccinate is excreted in large amount in urine.The severity of symptoms varies greatly, it is hard to evaluate the effect of therapy – useful is dietary restriction of nitrogen.Arginase deficiency (argininemia)Rare autosomal recessive disorder that cause many abnormalities in development and function of CNS.
23. Disorders of urea cycleDeficiency in any of urea cycle enzymes would results in hyperammonemia.Hepatic coma ( acquired hypeammonemia )In diseases of liver hepatic failure can finally lead to hepatic coma and death.Hyperammonemia is the failure of liver. The condition is also known as portal systemic encephalopathy.
24. Enzyme deficiencyAccumulation and excretion of arginine in urine and arginine precursors and products of arginine metabolism.Therapy – low nitrogen compounds diet (including essential amino acids
25. Disorders of urea cycleThe signs and symptoms are mainly pertaining to CNS dysfunction or manifestations of failure of liver function.The normal urea level in plasma is from 20 to 40 mg/dl.Urinary excretion of urea is 15 to 30 g/day. This corresponds to the breakdown of 40 to 80 g of proteins per day. Urea constitutes 80% of urinary organic solids.
26. Significance toxic ammonia is converted into non-toxic urea. polyamines have diverse role in cell growth and proliferation. synthesis of semi-essential amino acid arginine.
27. Symptoms blurring of vision nausea vomiting neurological deficits mental retardation coma & death
28. Diagnosis increased level of ammonia in blood and urine increased glutamine in CSF excreted in urine decreased blood urea level