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Digestion And Metabolism > Ammonia Metabolism And Urea Cycle > Flashcards

Ammonia Metabolism And Urea Cycle Flashcards

1
Q

What are the uses of catabolism of amino acids?

A
  1. Carbon skeketon: glucogen8c or ketogenic amino acids

2. Ammonia formation & urea cycle

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2
Q

Describe the transport of nitrogen from peripheral tissues

A
  • Ammonia is neurotoxic
    • Creates requirement for a non-toxic transport form of ammonia
  • N must be transported from peripheral tissues in a non-toxic form
    • Glutamine (Incorporation of NH3 to glutamate)
    • Alanine (Transport form of NH3 from muscle)
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3
Q

Aside from urine, where may ammonia/ammonium ve excreted?

A

All of our ammonia NH3/NH4+waste may not be directly excreted in the urine

  • In solution, ammonia is associated with many water molecules
  • If all metabolic ammonia is excreted in the urine, large obligate water losses would occur
  • Also, ammonia is neurotoxic. Hence, must be converted to UREA
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4
Q

How is ammonia transported?

A
  • Glutamine formed in most tissues (Brain):
  • Synthesized from glutamate
  • Enzyme: glutamine synthetase
  • Alanine: Synthesized in muscle
  • Transamination from pyruvate
  • Enzyme: ALT
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5
Q

Describe the aminotransferase reaction

A
  • Most amino acids undergo transamination with α-KG as the amino acceptor
  • Glutamate then becomes a central player in carrying nitrogen groups in most tissues
  • Free ammonia is not released
  • Amino group transfer
  • ALT and AST – Review from DLA
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6
Q

Explain ammonia formmation in liver

A
  • From Alanine and other amino acids
  • Transamination: Requires amino acid transaminase (PLP as coezyme)
  • Amino group is first transferred to α-keto-glutarate to form glutamate
  • From Glutamate
  • Oxidative deamination by Glutamate dehydrogenase forms free ammonia • Review from DLA
  • From glutamine
  • By glutaminase reaction, free ammonia and glutamate are formed
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7
Q

How important is ammonia formation in the gut?

A

Cirrhosis increases the amount of ammonia entering systemic circulation

Bacterial ureases form ammonia in colon.
Ammonia enters portal circulation and is delivered to liver and forms urea in the liver.

Intestinal ammonia formation becomes significant in patients with liver disease (ammonia not detoxified) → Ammonia enters systemic circulation resulting in neurotoxicity

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8
Q

Summarize the urea cycle

A

•Urea is not charged – needs less water to stay in solution than NH3/NH4+

  • Takes place in liver
  • Partly mitochondrial (two reactions) and partly cytosolic (three reactions)
  • Urea contains two nitrogen atoms
  • First N atom of urea donated by Ammonia & second N atom donated by Aspartate
  • Remember sources of ammonia and the formation of aspartate from oxaloacetate
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9
Q

What are the reactions of the urea cycle?

A 
1 – CPS-I: Carbamoyl phosphate synthetase-I
• Mitochondrial
• Activated by N-acetyl glutamate (NAG)
• Incorporates free ammonia
• (Do not confuse with CPS-II and CPT-I)

2 - OTC: Ornithine transcarbamoylase
• Mitochondrial

3 - ASS: Argininosuccinate synthetase
• Uses Aspartate

4 - ASL: Argininosuccinate lyase

5 - ARG: Arginase
• Forms Urea

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10
Q

What are the inherited disorders of the urea cycle?

A
  • Deficiency of an enzyme results in accumulation of the SUBSTRATE of that enzyme
  • All Urea cycle disorders characterized by increased blood ammonia levels (hyperammonemia) and elevated blood glutamine levels
  • Deficiency of CPS1, or OTC (the first two enzymes) results in the most severe hyperammonemia
  • In all the disorders, urea formation is decreased
  • In many cases, hyperammonemia symptoms appear during the first few days of life:
  • Lethargy
  • Irritability
  • Feeding difficulties
  • Respiratory alkalosis (Ammonia stimulates respiratory center→hyperventilation)
  • Neurological manifestations, seizures and intellectual disability and developmental delay if untreated
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11
Q

Describe hyperammonia type 1

A

CPS 1Deficiency

Hyperammonemia (most severe); Low levels of all urea cycle intermediates

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12
Q

Describe Hyperammonia type 2

A

OTC Deficiency

  • X-linked
  • Most common

Hyperammonemia, Increased orotic acid excretion in urine (Explain)

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13
Q

Describe Citrullinemia

A

Argininosuccinate synthetase deficiency

Hyperammonemia, Increased citrulline levels

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14
Q

Describe Argininosuccinic aciduria

A

Argininosuccinate lyase (ASL) deficiency

Hyperammonemia; Increased argininosuccinate levels

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15
Q

Describe argininemia

A

Arginase deficiency

Mild hyperammonemia; Increased arginine levels

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16
Q

How is hyperammonemia managed?

A
  • Dialysis: acute emergency situation
  • Administration of benzoic acid and or Phenylbutyrate / phenylacetate (alternate routes of N excretion)
  • Benzoic acid forms Hippuric acid by combining with glycine • Phenylacetate forms phenylacetylglutamine
  • Excreted in urine
  • Low protein / high carbohydrate • Minimize N intake
  • Prevention of stresses that induce a catabolic state
  • Long term: Liver transplantation
17
Q

How can phenylbutyrate be used to manage hyperammonia?

A 
Administration of phenylbutyrate:
– Converted to phenylacetate
– Condenses with glutamine
– Formsphenylacetylglutamine
– Excreted in urine

Phenylacetylglutamine

  • excreted in urine
  • removes 2 nitrogen atoms per molecule

Phenylbutyrate— forms phenylacetate—> phenylacetyl CoA and glutamine—> phenylglutamine

18
Q

Describe arginine administration

A

• For all the UCD (except, for arginase deficiency):

  • Treatment may include arginine administration:
  • It is something that might be attempted; If it doesn’t help it is discontinued
  • Sometimes allows urea cycle to progress by elevating the levels of all the substrates in the cycle
  • Arginine→Ornithine (arginase enzyme)
  • So substrates are more available
  • Might allow an enzyme that has lower substrate affinity to function
  • Also, activates NAG synthesis (NAG is allosteric activator of CPS-I)
19
Q

What is the impact of CPS 1 deficiency?

A

CPS-1 deficiency (Type I Hyperammonemia)

  • Very high blood ammonia levels; Most severe
  • Low levels of ALL urea cycle intermediates
  • Sometimes responds to Arginine supplements
  • Rationale: Arg stimulates formation of N-acetylglutamate • High levels of NAG might stimulate deficient CPS-I
  • Remember, NAG (Allosteric activator of CPS-I)
20
Q

Explain OTC deficiency

A 
OTC deficiency (X-linked)
• Hyperammonemia Type II
  • Most common UCD
  • Usually seen in males, and more severe in males (X-linked)
  • Mitochondrial ornithine transcarbamoylase
  • Normally:
  • OTC Combines ornithine and carbamoyl phosphate to form citrulline • Citrulline is transported to the cytoplasm
  • Citrulline combines with aspartate to form arginosuccinate
21
Q

What is the impact of Ornithine transcarbamoylase deficiency(OTC)?

A

Type 2 hyperammonemia

  • Elevated serum ammonia
  • Elevated serum & urine Orotic acid

Leads to

Orotic aciduria

Elevated carbamoyl phosphate drives Pyrimidine biosynthesis –
Orotic acid elevated in serum & urine

Treatments listed previously – of course

22
Q

How is arginosuccinate synthetase deficuency (citrullinemia)?

A
  • Diagnosis: hyperammonemia, with very high levels of serum citrulline, and citrulline in the urine
  • Treatments listed previously (of course)
23
Q

What is the effect of argininosuccinate lyase deficiency (Argininosuccinic aciduria)?

A

Argininosuccinate lyase deficiency (Argininosuccinic aciduria)

  • Differential diagnosis of hyperammonemia
  • Argininosuccinate elevated in plasma and urine
  • Also, elevated citrulline (because it is before the block)
  • Arginosuccinate in urine
  • Treatments listed previously – of course
24
Q

What is the effect of arginase deficiency?

A

Arginase deficiency (Hyperargininemia) • Elevated serum ammonia and elevated arginine

  • Blood NH3 levels not as high as other UCD
  • Treatment includes diet of essential amino acids excluding arginine
  • Other treatments previously listed (of course)
  • Significant number of cases are adult onset
  • Associated with neurological problems
25
Q

What is the fate of urea?

A
  • Urea is transported to the kidney where it is excreted in urine
  • Some urea is degraded in the gut, the ammonia reenters circulation and the liver must detoxify it
  • Renal failure leads to elevated BUN (Blood urea nitrogen)
  • UCD leads to elevated blood ammonia
26
Q

Describe hyperammonemia

A
  • Liver disease due to viral or drug induced hepatitis, alcoholic cirrhosis
  • In cirrhosis, there is porto-systemic shunting of blood
  • Portal blood enters the systemic circulation without going to the liver
  • Ammonia produced in intestine directly enters circulation and results in neurotoxicity
27
Q

Describe the treatment of hyperammonemmia

A
  • Low-protein/high carb diet→intuitive
  • Less N ingested, less needed to dispose
  • Lactulose→A disaccharide
  • Resistant to digestion in the small intestine
  • Normal flora digest lactulose, produce lactic acid, lactic acid is neutralized by NH4+ • More N excreted in the feces
  • Neomycin→(or other antibiotic treatment)
  • Reduction in bacterial urease in the gut
  • Might use some of the other treatments previously discussed
28
Q

What is the mechanism of ammonia neurotoxicity?

A

Mechanism of ammonia neurotoxicity is complex Hyperammonemia interferes with

  • Balance of neurotransmitters (Imbalance of excitatory and inhibitory neurotransmission)
  • Brain ATP metabolism

Brain CT shows widespread loss of cortical
sulci and gray-white differentiation, in
keeping with cerebral edema

29
Q

Summarize the ammonia neurotoxicity

A

Hyperammonemia enhances inhibitory neurotransmission
Glutamate [Excitatory]

Then via glutamine decarboxylase

y-aminobutyruc acid (GABA) (inhibitory)

Main point: Hyperammonemia alters neurotransmitter balance in the brain (Excitatory vs Inhibitory)

30
Q

What are the effects of elevated blood ammonia on generation of ATP?

A

Effects of elevated blood ammonia on generation of ATP:

  • α-ketoglutarate is converted to glutamate
    • Via glutamate dehydrogenase enzyme
    • Depletion of TCA cycle intermediates
    • Decreased TCA cycle activity
    • Reduced ATP synthesis
    • Don’t forget, your brain needs ATP
  • Reduced Na+/K+ ATPase activity
    • Osmotic pressure, edema
    • Alters neurotransmissio

Digestion And Metabolism (57 decks)

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