Amino Acid Catabolism

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Amino Acid Catabolism

• Disposal of Nitrogen and Carbon Skeletons

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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 NH4 240 uM (25-40 normal)
• hyperammonemia
• mild alkalosis (pH7.5, normal 7.35-7.45)

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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)

4
Clinical Case Study

• Oral therapy initiated
• EAA arginine
• Sodium benzoate
• Patient improves after 7 days
• Plasma NH4 normalized

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Overview of Amino Acid CatabolismInterorgan
Relationships
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Overview of Amino Acid CatabolismInterorgan
Relationships

• Intestine
• Dietary amino acids absorbed
• Utilizes glutamine and asparagine as energy
  sources
• Releases CO2, ammonium, alanine, citrulline as
  endproducts
• Utilizes glutamine during fasting for energy
• Dietary amino acids and catabolites released to
  portal blood

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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

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Overview of Amino Acid CatabolismInterorgan
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 ( of total aa) in BCAA (2-3X)

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Overview of Amino Acid CatabolismInterorgan
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 NH4
• a-KG for gluconeogenesis
• NH4 excreted or used for urea cycle (arginine
  synthesis)
• Important buffer preventing acidosis
• NH4 NH3 100 1

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Overview of Amino Acid CatabolismInterorgan
Relationships
11
Vitamin-Coenzymes in Amino Acid Metabolism

• Vitamin B-6 (pyridoxal phosphate)
• Folic acid (tetrahydrofolate)
• Vitamin B-12

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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

13
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

14
Vitamin-Coenzymes in Amino Acid Metabolism

• Vitamin B-12
• Catabolism of BCAA
• Methyl-malonyl CoA mutase (25-9 10)

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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 -gt Met requires B-12

Figure 26-4
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Overview of Amino Acid CatabolismInterorgan
RelationshipsHow does this occur?
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Disposal of Amino Acids Nitrogen Key reactions

• Transamination reactions
• Deamination reactions
• Glutamate dehydrogenase
• Hydrolytic deamination
• Glutaminase
• Glutamine synthesis

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Disposal of Amino GroupsTransamination Reactions

• Often the first step of amino acid degradation
• Transfer of amino group from many amino acids to
  limited number of keto acid acceptors
• Pyruvate lt-gt alanine
• Oxaloacetate lt-gt aspartate
• Alpha-keto-glutarate lt-gt glutamate

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Disposal of Amino GroupsTransamination Reactions

• Transamination reactions tend to channel amino
  groups on to glutamate
• Glutamates central role in amino acid N
  metabolism

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Disposal of Amino GroupsTransamination 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

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Disposal of Amino GroupsDeamination Reactions

• Glutamate dehydrogenase
• oxidative deamination
• Important in liver where it releases ammonia for
  urea synthesis
• Hydrolytic deamination
• Glutaminase asparaginase

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Disposal of Amino GroupsGlutamine 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

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Overview of Amino Acid CatabolismInterorgan
Relationships
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Movement of amino acid nitrogenpost-absorptive
and fasting states

• From extra-hepatic tissues (muscle) to liver
• Site of gluconeogenesis and ketogenesis
• Site of urea synthesis
• All amino acids present in plasma but enriched
  (50) in alanine and glutamine

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Production of ALA GLN in extrahepatic tissues

• Transamination of AA to form GLU
• AA aKG lt-gt aKA GLU
• Formation of ALA
• GLU pyr lt-gt aKG ALA
• Formation of GLN
• GLU lt-gt aKG NH3
• NH3 GLU -gt GLN

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Overview of Amino Acid CatabolismInterorgan
Relationships
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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

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Detoxification of Ammonia by the Liver the Urea
Cycle

• Contains all enzyme of urea cycle
• Site of urea synthesis
• Kidney has all urea cycle enzymes except arginase
• Site of arginine synthesis
• Mitochondria
• CPS regulatory enzyme

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Flow of Nitrogen from Amino Acids to Urea in Liver

• Amino acid flow from muscle to liver
• Alanine glutamine
• Liver
• Transfers N to GLU
• GLNase GDH
• Transaminases
• Transfers GLU-N to
• ASP
• AST
• Transamination route
• NH3
• GDH
• Trans-deamination route
• GLNase
• Transfers N to urea

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Ammonia detoxification by the liver

• Liver very effective at eliminating ammonia from
  blood
• Portal blood ammonia 300 1000 uM
• Systemic blood ammonia 20uM
• Periportal hepatocytes
• Urea synthesis
• Km CPS 1mM
• Perivenous hepatocytes
• Glutamine synthesis
• Very low Km for ammonia
• Removes any NH3 not removed by periportal
  hepatocytes

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33
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 NH4 240 uM (25-40 normal)
• hyperammonemia
• mild alkalosis (pH7.5, normal 7.35-7.45)

34
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)

35
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

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Detoxification of Ammonia by the Liver the Urea
Cycle
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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

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Resolution of Clinical Casesource of orotic acid
39
Clinical Case Study

• Treatment
• Oral therapy essential amino acids
• arginine
• sodium benzoate
• _at_7 days clinically well
• normal NH4

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Resolution of Clinical CaseTreatment

• 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
• Glycine synthase
• CO2 Me-THF NADH NH3 gt glycine
• removal results in reducing ammonia levels

41
Resolution of Clinical CaseGenetics

• Gene for OTC found on X-chromosome
• Women are carriers
• usually asymptomatic
• may experience migraines, vomiting, lethargy when
  eating high protein meals (meat)
• OTC deficiency most common (but rare) disorders
  of the urea cycle (1 20-80,000)