catabolism of amino acid

7/30/2019 Catabolism of Amino Acid

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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 (pH=7.5, 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/mgcreatinine (0.3-10)


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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 Catabolism:

Interorgan Relationships


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Intestine Dietary amino acids absorbed

Utilizes glutamine and asparagine as energysources 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 therapeuticnutritional that contains a

patented blend ofarginine, glutamine, andHMB (beta-hydroxy-beta-methylbutyrate). JUVENhas been clinically shownto help build lean bodymass (LBM),1,2 enhanceimmune response,2 andpromote collagen

synthesis


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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 (% of total aa) in BCAA (2-3X)


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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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Vitamin-Coenzymes

in Amino Acid Metabolism

Vitamin B-6 (pyridoxal phosphate)

Folic acid (tetrahydrofolate)

Vitamin B-12


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Vitamin-Coenzymes


Vitamin B-6 : pyridoxalphosphate

Enzymes that bind aminoacids use PLP as

coenzyme for binding

Transaminases

Amino acid

decarboxylases

Amino acid deaminases


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Vitamin-Coenzymes


Folacin:Tetrahydrofolate

(THF) 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

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 -> Met requires B-

12

Figure 26-4


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How 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 Groups:

Transamination Reactions

Often the first step of amino acid degradation

Transfer of amino group from many amino acidsto limited number of keto acid acceptors Pyruvate alanine

Oxaloacetate aspartate

Alpha-keto-glutarate glutamate


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


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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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Deamination Reactions

Glutamate dehydrogenase oxidative deamination

Important in liver where it releases ammonia for urea

synthesis

Hydrolytic deamination Glutaminase & asparaginase


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Glutamine Synthetase

Important plasma transport form of nitrogen frommuscle

Detoxification of ammonia Brain

Liver Removes ammonia intestinal tract

Bacterial deamination of amino acids

Glutamine utilization in intestinal cells


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Movement of amino acid nitrogen:

post-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 aKA + GLU

Formation of ALA GLU + pyr aKG + ALA

Formation of GLN

GLU aKG + NH3

NH3 + GLU -> GLN


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Detoxification of Ammonia by the

Liver: the Urea Cycle

Amino acid N flowing to liver as:

Alanine & glutamine

Other amino acidsAmmonia (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 ureacycle enzymes except

arginase

Site of arginine

synthesis

Mitochondria CPS regulatory

enzyme

f f


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Flow of Nitrogen from Amino

Acids to Urea in Liver

Amino acid flow from muscle toliver 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

A i d ifi i


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Ammonia detoxification

by the liver

Liver very effective ateliminating ammonia fromblood 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 notremoved by periportalhepatocytes


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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 (pH=7.5, 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)


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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 Ammoniaby 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


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Clinical Case Study

Treatment

Oral therapy essential amino acids

arginine

sodium benzoate

@7 days clinically well normal NH4

+

R l ti f Cli i l C


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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 Glycine synthase

CO2 + Me-THF + NADH + NH3 => glycine

removal results in reducing ammonia levels

R l ti f Cli i l C


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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)

OTC deficiency most common (but rare)disorders of the urea cycle (1: 20-80,000)

catabolism of amino acid

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