Amino Acid Metabolism Lecture Notes PDF

LECTURER: DR OJ POOE AMINO ACID METABOLISM MAJOR CONCEPTS TO BE UNDERSTOOD 1. Dietary proteins are the primary source of biologically useful nitrogen in our bodies. 2. The general scheme for the further metabolism of "digested" amino acids involves the transfer of the amino group to alpha­...

LECTURER: DR OJ POOE AMINO ACID METABOLISM MAJOR CONCEPTS TO BE UNDERSTOOD 1. Dietary proteins are the primary source of biologically useful nitrogen in our bodies. 2. The general scheme for the further metabolism of "digested" amino acids involves the transfer of the amino group to alpha­ketoglutarate forming glutamate plus an alpha­keto acid. 3. The glutamate produced is transported to liver mitochondria and deaminated by glutamate dehydrogenase. 4. Glutamine and alanine transport ammonia formed in other tissues to the liver. 5. Nitrogen is excreted as ammonia or urea. High serum levels of ammonia could indicate liver disease. Removal and disposal of amino acid nitrogen The removal of nitrogen from amino acids (deamination) results in the production of ammonia Ammonia is highly toxic and is therefore converted to non-toxic and highly soluble urea by the liver The urea is excreted in urine Since the main site of ureagenesis in the body is the liver, ammonia produced in other tissues is transported in the blood mainly as glutamine and alanine Removal and disposal of amino acid nitrogen Amino acids that need their nitrogen to be removed are extracted from the blood by the liver and deaminated so that ammonia is produced in the organ where it can be detoxified by its conversion to urea Quantitatively the most important route of amino acid deamination is the transfer of amino groups from various amino acids to α-ketoglutarate (2- oxoglutarate) to form glutamate (transamination)  The amino group is then removed from Removal and glutamate as ammonia by glutamate disposal of dehydrogenase (oxidative deamination) amino acid Glutamate dehydrogenase is the only amino nitrogen acid dehydrogenase with significant activity in the body Other reactions that produce ammonia in the body: i. The hydrolysis of side-chain amides of asparagine and glutamine by asparaginase and glutaminase which yield aspartate and glutamate, respectively ii. Deamination of histidine by histidinase (histidine ammonia lyase) which yields ammonia and urocanate) Other reactions iii) Pyridoxal-5-phosphate dependent dehydration of serine and threonine that produce catalysed by serine dehydratase which yields ammonia in the pyruvate and α- ketobutyrate, respectively, and ammonia body: Other reactions that produce ammonia in the body: iv. The purine nucleotide cycle which operates in the muscle. The reaction where AMP is coverted to IMP, there is release of ammonia Other reactions that produce ammonia in the body: L and D amino oxidase reactions - the D amino acid oxidase is mainly found in the kidney The function of this enzyme maybe to racemize D-amino acids to L- amino acids which are the form used by enzyme systems in the body The reaction produces α-keto acid then the amino group is added in L-configuration by L-aminotransferase in the body The sources of D amino acids can be from the diet or gut bacteria L and D amino oxidase reactions The Urea Cycle The two nitrogens in urea are derived from ammonia and aspartate and the carbon from bicarbonate. Some of the reactions from the urea cycle take place in the mitochondrion and others in the cytosol The glutamate dehydrogenase reaction that feeds ammonia into the cycle also takes place in the mitochondrion.  The Urea Cycle The ammonia released by mitochondrial enzyme, glutamate dehydrogenase reacts with ammonia to form the carbamoyl group which is activated to carbamoyl phosphate in the same reaction This reaction is catalysed by carbamoyl phosphate synthetase I (CPS1) It is different from CPSII the cytosolic enzyme that generates carbamoyl phosphate for pyrimidine biosynthesis CPS1 activation by NAG Note that two molecules of ATP are used in this reaction. One is used to provide energy for the synthesis of the carbamoyl group and the other for its activation CPSI is allosterically activated by N- acetyl glutamate (NAG) which is synthesized in large quantities when there is a large scale deamination of amino acids. High concentrations of arginine stimulate CPSI The ‘carrier’ molecule in the urea cycle is ornithine (like oxaloacetate in the TCA cycle). Ornithine reacts with carbamoyl phosphate to give citrulline in a reaction catalysed by ornithine transcarbamoylase The Urea Cycle The ornithine/citrulline transporter on the inner mitochondrial membrane exchanges the two compounds. Citrulline leaves the mitochondrion such that further reactions of the urea cycle take place in the cytosol The reaction catalysed by argininosuccinate synthetase acquires the second nitrogen of urea from aspartate (Note the input of energy in this synthetic reaction Argininosuccinate lyase then eliminates fumarate from the asparate moiety of argininosuccinate leaving the amino group as part of the resulting product, arginine The final reaction is the hydrolysis of arginine by arginase which releases urea and regenerates the carrier molecule, ornithine Note the links between the urea cycle, glycolysis, and TCA cycle via pyruvate, oxaloacetate, α-ketoglutarate and fumarate Control of the urea cycle i. Via substrate viability, allosteric regulation of CPS1 by N-acetylglutamate and induction of urea cycle enzymes ii. Induction of urea cycle enzymes will occur as a result of high protein diets or prolonged fasting or starvation when there is large protein breakdown Defects of the urea cycle Defects can occur with any of the enzymes. General characteristics include: mental retardation, seizures coma and early death The more lethal enzyme deficiencies are at the beginning of the cycle such as CPS1 and ornithine transcarbamoylase These will usually result in high, levels of ammonia. in blood – hyperammonemia Some defects can be managed by dietary intervention depending on the inheritance pattern and some require enzyme replacement