Amino Acid Catabolism 2
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Amino Acid Catabolism 2

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    Amino Acid Catabolism 2 Amino Acid Catabolism 2 Presentation Transcript

    • Amino Acid Catabolism Disposal of Nitrogen and Carbon Skeletons
    • Overview of Amino Acid Catabolism: Interorgan Relationships
      • Intestine
        • Dietary amino acids absorbed
        • Utilizes glutamine and asparagine as energy sources
          • Releases CO 2 , ammonium, alanine, citrulline as endproducts
          • Utilizes glutamine during fasting for energy
        • Dietary amino acids and catabolites released to portal blood
    • Enteral Formulas containing glutamine
      • JUVEN is a therapeutic nutritional that contains a patented blend of arginine, glutamine, and HMB (beta-hydroxy-beta-methylbutyrate). JUVEN has been clinically shown to help build lean body mass (LBM), 1,2 enhance immune response, 2 and promote collagen synthesis
    • Overview of Amino Acid Catabolism: Interorgan Relationships
    • Overview of Amino Acid Catabolism: Interorgan Relationships
      • Liver
        • Synthesis of liver and plasma proteins
        • Catabolism of amino acids
          • Gluconeogenesis
          • Ketogenesis
          • Branched chain amino acids not catabolized
          • Urea synthesis
        • Amino acids released into general circulation
          • Enriched in BCAA (2-3X)
    • Overview of Amino Acid Catabolism: Interorgan Relationships
    • Overview of Amino Acid Catabolism: Interorgan Relationships
      • Skeletal Muscle
        • Muscle protein synthesis
        • Catabolism of BCAA
          • Amino groups transported away as alanine and glutamine (50% of AA released)
            • Alanine to liver for gluconeogenesis
            • Glutamine to kidneys
      • Kidney
        • Glutamine metabolized to a-KG + NH 4
          • a-KG for gluconeogenesis
          • NH 4 excreted or used for urea cycle (arginine synthesis)
            • Important buffer from acidosis
    • Overview of Amino Acid Catabolism: Interorgan Relationships
    • Vitamin-Coenzymes in Amino Acid Metabolism
      • Vitamin B-6 : pyridoxal phosphate
        • Enzymes that bind amino acids use PLP as coenzyme for binding
          • Transaminases
          • Amino acid decarboxylases
          • Amino acid deaminases
    • Vitamin-Coenzymes in Amino Acid Metabolism
      • Folacin: Tetrahydrofolate (THF)
        • Carrier of single carbons
          • Donor & receptor
          • Glycine and serine
          • Tryptophan degradation
          • Histidine degradation
          • Purine and pyrimidine synthesis
    • Vitamin-Coenzymes in Amino Acid Metabolism
      • Vitamin B-12
        • Catabolism of BCAA
          • Methyl-malonyl CoA mutase (25-9 &10)
    • Vitamin-Coenzymes in Amino Acid Metabolism
      • Vitamin B-12
        • Methionine synthesis/recycling
          • Methionine as a methyl donor
            • Choline and creatine synthesis
            • Homocysteine is product
            • HCys -> Met requires B-12
    • Disposal of Amino Groups: Transamination Reactions
      • Generally the first step of amino acid degradation
      • Transfer of amino group from many amino acids to limited number of keto acid acceptors
        • Pyruvate -> alanine
        • Oxaloacetate -> aspartate
        • Alpha-keto-glutarate -> glutamate
    • Disposal of Amino Groups: Transamination Reactions
      • Transamination reactions tend to channel amino groups on to glutamate
        • Glutamate’s central role in amino acid N metabolism
    • Disposal of Amino Groups: Transamination Reactions
      • Transaminase reactions are reversible
        • ALT = SGOT
          • ALA important in muscle where ~25% of AA-N is transported out on ALA
          • In liver, reverse reaction moves AA-N back on GLU
        • AST = SGPT
          • ASP important in liver since half of urea-N is from ASP
    • Disposal of Amino Groups: Deamination Reactions
      • Glutamate dehydrogenase
        • oxidative deamination
        • Important in liver where it releases ammonia for urea synthesis
      • Hydrolytic deamination
        • Glutaminase & asparaginase
    • Disposal of Amino Groups: Glutamine Synthetase
      • Important plasma transport form of nitrogen from muscle
      • Detoxification of ammonia
        • Brain
        • Liver
          • Removes ammonia intestinal tract
            • Bacterial deamination of amino acids
            • Glutamine utilization in intestinal cells
    •  
    • Clinical Case Study
      • Male infant, 2.9 kg at birth, healthy
      • Day 3 - seizures
      • Mother with history of aversion to meat
        • vomiting and lethargy
      • mild alkalosis (pH=7.5, normal 7.35-7.45)
      • plasma NH 4 + = 240 uM (25-40 normal)
    • Clinical Case Study
      • Plasma AA
        • gln = 2400 uM (350-650)
        • ala = 750 uM (8-25)
        • arg = 5 uM (30-125)
        • cit = undetectable
      • Urinary orotic acid = 285 ug/mg creatinine (0.3-10)
    • Clinical Case Study
      • Treatment
        • Oral therapy essential amino acids
        • arginine
        • sodium benzoate
      • @7 days clinically well
        • normal NH 4 +
    • Overview of Amino Acid Nitrogen Metabolism: moving amino acid nitrogen to the liver safely
      • Catabolism of amino acids results in:
        • Carbon skeleton
          • Source for energy
          • Gluconeogenesis or fat synthesis in liver
        • Nitrogen
          • Excreted as urea, synthesized in liver
      • Muscle
        • Move most N onto ALA and GLN for transport to liver
      • Liver
        • Move N from ALA and GLN onto ASP and NH 3 for urea synthesis
    • Detoxification of Ammonia by the Liver: the Urea Cycle
      • Amino acid N flowing to liver as:
        • Alanine & glutamine
        • Other amino acids
        • Ammonia (from portal blood)
      • Urea
        • chief N-excretory compound
    • Detoxification of Ammonia by the Liver: the Urea Cycle
        • Liver
        • Contains all enzyme of urea cycle
        • Site of urea synthesis
    • Flow of Nitrogen from Amino Acids to Urea in Liver
      • Amino acid flow from muscle to liver
        • Alanine & glutamine
      • Liver
        • Transfers N to GLU
          • GLN’ase
          • Transaminases
        • Transfers GLU-N to:
          • ASP
            • AST
              • Transamination route
          • NH3
            • GDH
              • Trans-deamination route
        • Transfers N to urea
    • Ammonia detoxification by the liver
      • Liver very effective at eliminating ammonia from blood
        • Portal blood ammonia = 300uM
        • Systemic blood ammonia = 20uM
      • Periportal hepatocytes
        • Urea synthesis
      • Perivenous hepatocytes
        • Glutamine synthesis
          • Very low Km for ammonia
    • Clinical Case Study
      • Male infant, 2.9 kg at birth, healthy
      • Day 3 - seizures
      • Mother with history of aversion to meat
        • vomiting and lethargy
      • plasma NH 4 + = 240 uM (25-40 normal)
        • hyperammonemia
        • mild alkalosis (pH=7.5, normal 7.35-7.45)
    • Clinical Case Study
      • Plasma AA
        • gln = 2400 uM (350-650)
        • ala = 750 uM (8-25)
        • arg = 5 uM (30-125)
        • cit = undetectable
      • Urinary orotic acid = 285 ug/mg creatinine (0.3-10)
    • Resolution of Clinical Case
      • Diagnosis of neonatal hyperammonemia
        • symptoms
        • blood ammonium concentration
      • Defect in urea cycle
        • elevated glutamine and alanine
        • low or absent arginine and citrulline
    • Resolution of Clinical Case
      • Genetic deficiency of ornithine transcarbamoylase
        • urinary orotic acid
          • CP spills into cytosol where enters pyrimidine biosynthetic pathway, orotic acid an intermediate in the pathway
    • Detoxification of Ammonia by the Liver: the Urea Cycle
    • Clinical Case Study
      • Treatment
        • Oral therapy essential amino acids
        • arginine
        • sodium benzoate
      • @7 days clinically well
        • normal NH 4 +
    • Resolution of Clinical Case: Treatment
        • Essential Amino Acids
        • Arginine
          • w/o urea cycle, becomes essential
        • Benzoic acid
          • conjugates with glycine and excreted in urine as hippuric acid
          • glycine in equilibrium with ammonia
          • removal results in reducing ammonia levels
    • Resolution of Clinical Case: Genetics
      • Gene for OTC found on X-chromosome
      • Women are carriers
        • usually asymptomatic
        • may experience migraines, vomiting, lethargy when eating high protein meals (meat)