Urea cycle and Amino Acid metabolism in LIver

Question 1

protein digestion

Answer 1

• takes place in stomach and SI
• pepsin cuts protein into peptides in stomach
• trypsin and chymotrypsin cut proteins and larger peptides into smaller peptides in SI
• Aminopeptidase and caboxypeptidases A and B degrade peptides into AA’s in SI
• AA’s are absorbed through epithelial cell intestinal mucosa of the villi and enter capillaries and are tranpsorted to liver
• Nitrogen cannot be stored and NH4+ is toxic, cannot be stored in liver.

Question 2

three circumstances AA’s undergo oxidative catabolism?

Answer 2

1. Leftover AA’s from normal protein turnover are degraded
2. Dietary AA’s that exceed body’s protein synthesis are degraded
3. Proteins in the the body are broken down to supply AA’s for catabolism when carbs are limited - i.e. starvation and DM

Question 3

Liver in AA catabolism

Answer 3

1. AA catabolism : nitrogen metabolism in urea, ammonia
2. AA detoxification : via Urea cycle

2 key processes in metabolic nitrogen elimination:

• transamination or aminotransferase rxns.
• release of nitrogen from glutamate and its conversion to urea by urea cycle in liver

Question 4

Glucose-Alanine cycle

Answer 4

Toxic ammonia formed in muscle from breakdown of muscle protein is transported to liver as alanine. alanine serves as a carrier or ammonia and of the carbon skeleton of pyruvate from skeletal muscle to liver. The ammonia is excreted and the pyruvate is used to produce glucose in the liver which is returned to the muscle.

Question 5

Enzymatic transamination

Answer 5

• All aminotransferases rely on the pyridoxal phosphate cofactor
• Typically, alph-ketoglutarate accepts amino groups
• L-Glutamine acts as a temporary storage of nitrogen
• L-Glutamine can donate the amino group when needed for amino acid biosynthesis

Question 6

How is ammonia transported safely in bloodstream?

Answer 6

• • transported as glutamine
• uneeded glutamine is processed in intestines, kidneys and liver
• Excess ammonia in tissues is added to glutamate to form glutamine, a process catalyzed by glutamine synthetase. After transport in the bloodstream, the glutamine enters the liver and NH4+ is liberated in mitochondria by the enzyme glutaminase

Question 7

4 steps of Urea cycle

Answer 7

1 Carbamoyl phosphate combined with ornithine to form citrulline (ornithine transcarbamoylase) in matrix, passes into the cytosol. Deficiency of Carbomoyl phophate synthetase I, results in inability to excrete nitrogen

2 Citrulline is converted to arginino- succinate (argininsuccinate synthetase) through a citrullyl-AMP intermediate (entry of the second amino group).

3 Argininosuccinate is cleaved (argininosuccinase) to yield fumarate & arginine which enters the citric acid cycle.

4 Formation of urea: arginine is converted to urea & ornithine (arginase)
Ornithine – product of the last reaction & substrate of first reaction (same as oxaloacetate in TCA)

Question 8

deficiency of cabomoyl phosphate synthetase I

Answer 8

inability to excrete nitrogen

Question 9

deficiency of ornithine transcarbomylase

Answer 9

no urea production, see high levels of ammonium in blood

Question 10

urea cycle reaction summary

Answer 10

NH4+ + CO2 + aspartate + 3 ATP —> urea + fumarate + 2 ADP + AMP + 4 Pi

Question 11

Enzymes found in mitochondria

Answer 11

1. Carbamoyl phosphate synthetase

2. Ornithine Trans carbamylase

Question 12

Enzymes found in cytosol

Answer 12

3. Arginino-Succinate Synthase
4. Arginino-succinase
5. Arginase

Question 13

Urea cycle facts

Answer 13

Found primarily in liver and lesser extent in kidney

• L-glutamine can be used to synthesize new amino acids, or it can dispose of excess nitrogen as ammonia
• toxic ammonia is quickly recaptured into carbamoyl phosphate and passed into the urea cycle
• Nitrogen added to the urea cycle via carbamoyl phosphate and aspartate

Question 14

Inherited defects in urea cycle enzymes

Answer 14

• Complete loss of a urea cycle enzyme causes death shortly after birth
• Deficiencies in urea cycle enzymes results in hyperammonemia (elevated ammonia levels in the blood).
• Most urea cycle disorders also lead to a build-up of glutamine and glutamate which function as osmolites that can cause brain swelling -neurological symptoms.
• Urea cycle disorders treated by restricting dietary protein as a means to limit nitrogen intake.

Question 15

arginosuccinase deficiency

Answer 15

• can be treated effectively by putting patients on a protein-depleted diet that is supplemented with high doses of L-arginine.

Question 16

Phenylketonuria (PKU)

Answer 16

• autosomal recessive metabolic genetic disorder characterized by deficiency of phenylalaline hydroxylase (PAH)
  = defective phenylalaline hydroxylase reaction results in no conversion of phenylalaline to tyrosine.
• Severe mental retardation occurs if the disorder is untreated.
• ADHD (attention-deficit hyperactivity disorder) appears to be the most common problem seen in those who do not stick to a very low-phenylalanine diet.

Question 17

What does PAH do?

Answer 17

PAH metabolizes amino acid phenylalanine to amino acid tyrosine and epinephrine.

Phenylalanine –> Tyrosine –> L-Dopa –> Dopamine –> Norepinephrine –> Epinephrine

Question 18

PAH deficiency

Answer 18

• phenylalanine accumulates and converted into phenylpyruvate .
• Both phenylalanine and phenylpyruvate are harmful to the central nervous system.
  Phenylalanine plays a role in production of melanin.

Question 19

NutraSweet (aspartame)

Answer 19

contains phenylalanine and aspartate. Any products containing aspartame should be avoided.

Question 20

BUN

Answer 20

= blood urea nitrogen

• A BUN test measures the amount of urea nitrogen in blood
• It reveals important information about kidneys and liver function
• The liver produces urea in the urea cycle as a waste product of the digestion of protein
• Normal human adult blood should contain between 6 to 20 mg or mmol/L of urea nitrogen per 10 ml (6–20mg/dL) of blood.

Question 21

Elevated BUN may indicate…

Answer 21

> 20 mg/dL

• Congestive heart failure
• Excessive protein levels in the gastrointestinal tract
• Gastrointestinal bleeding,Hypovolemia (dehydration)
• Kidney disease, including glomerulonephritis, pyelonephritis, and acute tubular necrosis, Kidney failure, Urinary tract obstruction, Shock

Question 22

Low BUN levels

Answer 22

<6 mg/dL

• Low protein diet
• Malnutrition
• Over-hydration

Question 23

ALT

Answer 23

Alanine transaminase
- An enzyme found mainly in liver cells, to metabolize protein. Normally, ALT levels in the blood are low. When the liver is damaged, ALT is released in the bloodstream and levels increase.

Question 23

AST

Answer 23

Aspartate transaminase
- The enzyme AST plays a role in metabolism of alanine. AST is found in high concentrations in liver cells. An increase in AST levels may indicate liver damage.

Question 23

hepatic encephalopathy

Answer 23

• In the setting of liver disease, particularly if blood is shunted away from the liver, ammonia catabolism is decreased, which may increase plasma levels considerably.
• increases in plasma ammonia
• treatment: reducing amonia load coming from colon and liver transplantation