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Almaaqal University Metabolism of Protein and Amino Acids Dr/ Wael Sobhy Darwish Biochemistry PhD Lec-11  AMMONIA (NH3) Definition - Ammonia is a toxic su...

Almaaqal University Metabolism of Protein and Amino Acids Dr/ Wael Sobhy Darwish Biochemistry PhD Lec-11  AMMONIA (NH3) Definition - Ammonia is a toxic substance especially to the central nervous system. - Any ammonia formed in the peripheral tissue must be moved to the liver to be converted into urea. NH3 is transported from peripheral tissues to the liver via formation of: Glutamine (most tissues) Alanine (muscle) BLOOD AMMONIA - Blood contains traces of ammonia: 10- 80 ug/dI.  Sources of ammonia 1. Transdeamination of amino acids: In many tissues, particularly liver 2- Glutamine: The kidneys form ammonia from glutamine by glutaminase enzyme. Most of this ammonia is used in regulation of Acid base balance. 3. Purines and pyrimidines metabolism. 4. Various nitrogenous compounds e.g.: monoamines that act as neurotransmitters. 5. In intestine: ammonia is produced by the action of bacterial enzymes on: a) Dietary amino acids. b) Urea secreted into the intestine.  Fate of ammonia 1. Formation of non-essential amino acids: Through Transdeamination. 2. Formation of glutamine: a) Glutamine synthetase is a mitochondrial enzyme present in many tissues as kidney and brain. b) Glutamine has the following functions: 1) Regulation of acid base balance: glutamine is deaminated by glutaminase, releasing ammonia again. Ammonia is used in regulation of acid base balance by the kidneys. 2) Removes the toxic effect of ammonia in brain: Ammonia + Glutamate → Glutamine. 3) Glutamine is the source of: N3 and N9 of purines bases. 4) Glutamine is used in detoxication of phenyl acetic acid (a toxic substance). 3. Formation of urea. 4. Excretion in urine  Ammonia Intoxication Definition: Excess ammonia which is toxic to the central nervous system. Symptoms: Include: A. Flapping tremors, slurring speech, blurring vision and vomiting in infancy. B. High concentration of ammonia may cause coma and death Types and causes of hyperammonemia A) Acquired hyperammonemia 1- Liver cell failure: The diseased liver cells cannot convert ammonia into urea. 2- Renal failure 3- Shunt operation between portal and systemic circulation. 4- Collaterals between portal and systemic circulation due cirrhosis of liver, hepatitis etc. B) Inherited hyperammonemia:- Result from genetic deficiency of one of five enzymes of urea cycle → Failure to synthesize urea → Hyperammonemia during the first week after birth → Mental retardation.  Mechanism of ammonia intoxication: At normal blood ammonia level, any ammonia reaches the brain incorporated into glutamine formation by glutamine synthetase enzyme. In cases of hyperammonemia, ammonia reacts not only with glutamate, but also with α- Ketoglutarate by glutamate dehydrogenase enzyme. This depletes α-Ketoglutarate which is an essential intermediate of citric acid cycle → Decrease in ATP and energy production → symptoms of ammonia intoxication → coma.  UREA Urea is the main end product of protein metabolism. Urea formation is the pathway through which the liver can convert toxic ammonia into non-toxic urea. SITE OF UREA FORMATION 1. Liver is the only site for urea formation. 2. Then urea is transported in the blood to the kidney to be excreted in urine PLASMA UREA 1. Plasma urea: is 15-45 mg/dl. 2. Diagnostic importance of plasma urea determination: a) Measurement of plasma urea is one of the kidney function tests. b) In kidney diseases as in renal failure, kidney fails to excrete urea → High blood urea concentration uremia).  UREA FORMATION It is also called Krebs’ Henseleit cycle. 1. The first two reactions occur in mitochondria where other reactions occur in cytosol. 2. Six amino acids share in urea cycle: ornithine, citrulline, arginosuccinate, Aspartate. And Arginine. The 6th one is N-acetyl glutamate that acts as allosteric activator of Carbamoyl phosphate synthase I. STEPS 1. Formation of Carbamoyl phosphate: a) This reaction occurs in mitochondria. b) It needs CO2 (a product of citric acid cycle), ammonia (a product of deamination of glutamate) and phosphate (from ATP). c) This reaction is catalyzed by Carbamoyl phosphate synthase I. It needs magnesium (Mg) ions, manganese (Mn++) and N-acetyl glutamate as activators. d) 2 ATP molecules are used in this reaction, one to provide phosphate and the other to supply energy.  2. Formation of citrulline: a) This reaction also occurs in mitochondria. b) Carbamoyl phosphate reacts with ornithine, in the presence of ornithine transcarbamylase enzyme producing citrulline. c) Citrulline then passes to cytosol. d) Ornithine is regenerated with each turn of urea cycle 3. Formation of arginosuccinate: a) Citrulline reacts with Aspartate in the cytosol to form arginosuccinate. 4. Cleavage of arginosuccinate: a) It is cleaved into Arginine and Fumarate. 5. Cleavage of Arginine into ornithine and urea a) Ornithine then passes to the mitochondria to start a new cycle. b) Urea passes to the blood to be excreted by the kidney in urine.  FATE OF α -KETO-ACIDS The α-ketoacid (the carbon skeleton) remaining after the removal of the amino group by transamination and deamination of amino acids may undergo: A. Reamination: by ammonia (NH3) to form again the corresponding amino acid (by glutamate dehydrogenase). B. Catabolized to form seven products: pyruvate, acetyl CoA, acetoacetyl CoA, Fumarate, oxaloacetate, α-Ketoglutarate and Succinyl CoA. C. These products enter different pathways which lead to: 1. Synthesis of glycogen or glucose. 2. Synthesis of lipids. 3. Complete oxidation into CO2 and H2O. glucogenic and ketogenic amino acids Glucogenic amino acids are convertible to glucose ketogenic amino acids are those that can enter a metabolic cycle to produce fatty acids and be stored as fat.