Transcript Amino Acid Catabolism 2

Amino Acid Catabolism
Disposal of Nitrogen and Carbon
Skeletons
Clinical Case Study
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Male infant, 2.9 kg at birth, healthy
Day 3 - seizures
Mother with history of aversion to meat
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vomiting and lethargy
plasma [NH4+] = 240 uM (25-40 normal)
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hyperammonemia
mild alkalosis (pH=7.5, normal 7.35-7.45)
Clinical Case Study
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Plasma AA
gln = 2400 uM (350-650)
 ala = 750 uM (8-25)
 arg = 5 uM (30-125)
 cit = undetectable
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Urinary orotic acid = 285 ug/mg
creatinine (0.3-10)
Clinical Case Study
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Oral therapy initiated
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EAA + arginine
Sodium benzoate
Patient improves after 7 days
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Plasma [NH4+] normalized
Overview of Amino Acid Catabolism:
Interorgan Relationships
Overview of Amino Acid Catabolism:
Interorgan Relationships
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Intestine
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Dietary amino acids absorbed
Utilizes glutamine and asparagine as energy
sources
Releases CO2, ammonium, alanine, citrulline as
endproducts
 Utilizes glutamine during fasting for energy
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Dietary amino acids and catabolites released
to portal blood
Enteral Formulas containing
glutamine
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JUVEN is a therapeutic
nutritional that contains a
patented blend of
arginine, glutamine, and
HMB (beta-hydroxy-betamethylbutyrate). 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
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Liver
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Synthesis of liver and plasma proteins
Catabolism of amino acids
Gluconeogenesis
 Ketogenesis
 Branched chain amino acids not catabolized
 Urea synthesis
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Amino acids released into general circulation
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Enriched (% of total aa) in BCAA (2-3X)
Overview of Amino Acid Catabolism:
Interorgan Relationships
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Skeletal Muscle
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Muscle protein synthesis
Catabolism of BCAA
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Amino groups transported away as alanine and glutamine
(50% of AA released)
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Alanine to liver for gluconeogenesis
Glutamine to kidneys
Kidney
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Glutamine metabolized to a-KG + NH4
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a-KG for gluconeogenesis
NH4 excreted or used for urea cycle (arginine synthesis)
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Important buffer preventing acidosis
[NH4+] : [NH3] = 100 : 1
Overview of Amino Acid Catabolism:
Interorgan Relationships
Vitamin-Coenzymes
in Amino Acid Metabolism
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Vitamin B-6 (pyridoxal phosphate)
Folic acid (tetrahydrofolate)
Vitamin B-12
Vitamin-Coenzymes
in Amino Acid Metabolism
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Vitamin B-6 : pyridoxal
phosphate
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Enzymes that bind amino
acids use PLP as
coenzyme for binding
Transaminases
 Amino acid
decarboxylases
 Amino acid deaminases
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Vitamin-Coenzymes
in Amino Acid Metabolism
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Folacin:
Tetrahydrofolate
(THF)
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Carrier of single
carbons
Donor & receptor
 Glycine and serine
 Tryptophan degradation
 Histidine degradation
 Purine and pyrimidine
synthesis
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Vitamin-Coenzymes in Amino
Acid Metabolism
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Vitamin B-12
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Catabolism of BCAA
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Methyl-malonyl CoA
mutase (25-9 &10)
Vitamin-Coenzymes in Amino
Acid Metabolism
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Vitamin B-12
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Methionine
synthesis/recycling
Methionine as a methyl
donor
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Choline and creatine
synthesis
Homocysteine is product
HCys -> Met requires B12
Figure 26-4
Overview of Amino Acid Catabolism:
Interorgan Relationships
How does this occur?
Disposal of Amino Acids Nitrogen:
Key reactions
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Transamination reactions
Deamination reactions
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Glutamate dehydrogenase
Hydrolytic deamination
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Glutaminase
Glutamine synthesis
Disposal of Amino Groups:
Transamination Reactions
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Often the first step of amino acid degradation
Transfer of amino group from many amino acids
to limited number of keto acid acceptors
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Pyruvate <-> alanine
Oxaloacetate <-> aspartate
Alpha-keto-glutarate <-> glutamate
Disposal of Amino Groups:
Transamination Reactions
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Transamination reactions tend to channel amino
groups on to glutamate
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Glutamate’s central role in amino acid N metabolism
Disposal of Amino Groups:
Transamination Reactions
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Transaminase reactions are reversible
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ALT = SGOT
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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
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ASP important in liver since half of urea-N is from ASP
Disposal of Amino Groups:
Deamination Reactions
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Glutamate dehydrogenase
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oxidative deamination
Important in liver where it releases ammonia for urea
synthesis
Hydrolytic deamination
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Glutaminase & asparaginase
Disposal of Amino Groups:
Glutamine Synthetase
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Important plasma transport form of nitrogen from
muscle
Detoxification of ammonia
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Brain
Liver
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Removes ammonia intestinal tract
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Bacterial deamination of amino acids
Glutamine utilization in intestinal cells
Overview of Amino Acid Catabolism:
Interorgan Relationships
Movement of amino acid nitrogen:
post-absorptive and fasting states
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From extra-hepatic tissues (muscle) to
liver
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Site of gluconeogenesis and ketogenesis
Site of urea synthesis
All amino acids present in plasma but
enriched (~50%) in alanine and glutamine
Production of ALA & GLN in
extrahepatic tissues
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Transamination of AA to form GLU
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Formation of ALA
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AA + aKG <-> aKA + GLU
GLU + pyr <-> aKG + ALA
Formation of GLN
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GLU <-> aKG + NH3
NH3 + GLU -> GLN
Overview of Amino Acid Catabolism:
Interorgan Relationships
Detoxification of Ammonia by the
Liver: the Urea Cycle
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Amino acid N flowing to liver as:
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Alanine & glutamine
Other amino acids
Ammonia (from portal blood)
Urea
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chief N-excretory compound
Detoxification of Ammonia by the
Liver: the Urea Cycle
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Contains all enzyme
of urea cycle
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Site of urea synthesis
Kidney has all urea
cycle enzymes except
arginase
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Site of arginine
synthesis
Mitochondria
CPS regulatory
enzyme
Flow of Nitrogen from Amino
Acids to Urea in Liver
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Amino acid flow from muscle to
liver
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Alanine & glutamine
Liver
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Transfers N to GLU
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GLN’ase & GDH
Transaminases
Transfers GLU-N to:
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ASP
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AST
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Transamination route
NH3
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GDH
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Trans-deamination route
GLN’ase
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Transfers N to urea
Ammonia detoxification
by the liver
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Liver very effective at
eliminating ammonia from
blood
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Periportal hepatocytes
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Portal blood ammonia = 300 –
1000 uM
Systemic blood ammonia =
20uM
Urea synthesis
Km CPS ~ 1mM
Perivenous hepatocytes
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Glutamine synthesis
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Very low Km for ammonia
Removes any NH3 not
removed by periportal
hepatocytes
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
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Diagnosis of neonatal
hyperammonemia
symptoms
 blood ammonium concentration
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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
Resolution of Clinical Case
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Genetic deficiency of ornithine
transcarbamoylase
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urinary orotic acid
 CP
spills into cytosol where enters
pyrimidine biosynthetic pathway, orotic acid
an intermediate in the pathway
Resolution of Clinical Case
source of orotic acid
Clinical Case Study
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Treatment
Oral therapy essential amino acids
 arginine
 sodium benzoate
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@7 days clinically well
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normal NH4+
Resolution of Clinical Case:
Treatment
Essential Amino Acids
 Arginine
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w/o urea cycle, becomes essential
Benzoic acid
conjugates with glycine and excreted in urine as
hippuric acid
 glycine in equilibrium with ammonia
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Glycine synthase
CO2 + Me-THF + NADH + NH3 => glycine
removal results in reducing ammonia levels
Resolution of Clinical Case:
Genetics
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Gene for OTC found on X-chromosome
Women are carriers
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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)