amino acid catabolism 2

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 CO2, ammonium, alanine, citrulline as

endproducts Utilizes glutamine during fasting for energy

Dietary amino acids and catabolites released to portal blood

Enteral Formulas containing glutamine

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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)


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 from acidosis

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


Folacin: Tetrahydrofolate (THF) Carrier of single

carbons Donor & receptor Glycine and serine Tryptophan degradation Histidine degradation Purine and pyrimidine

synthesis


Vitamin B-12 Catabolism of BCAA

Methyl-malonyl CoA mutase (25-9 &10)


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 NH4

+ = 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 NH4

+

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 NH3 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


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 NH4+ = 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

Clinical Case Study

Treatment Oral therapy essential amino acids arginine sodium benzoate

@7 days clinically well normal NH4

+

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)

amino acid catabolism 2

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