Urea Cycle

Question 1

3 reasons for amino acid oxidation (catabolism)

Answer 1

1. Proteins have a half-life…constant turnover of proteins…proteins broken down into amino acids and excess ones are degraded (since they cannot be stored)
2. Excess amino acids from a high protein diet
3. Prolonged fasting or starvation (or uncontrolled diabetes)…proteins are catabolized for energy

Question 2

Fate of amino acids (3 general steps)

Answer 2

1. Amino group is removed as ammonia…leaving the ketoacid carbon skeleton
2. Ammonia is converted into urea in the urea cycle
3. Ketoacid is oxidized, and converted to useful products

Question 3

All transamination reactions are readily (?) and require what cofactor?

Answer 3

Reversible

Pyridoxal phosphate (PLP)

Question 4

L-glutamate transamination

Answer 4

—> alpha-KG

Question 5

Sources of NH4 from muscle

Answer 5

Alanine and glutamine

**glutamine is also a source from extrahepatic tissues

Question 6

Excess amino acids are processed where? And what is their ultimate fate

Answer 6

In liver

Amino groups are transferred from amino acid through series of transamination and non-transamination reactions

Ultimately producing NH4 for the urea cycle

Question 7

Amino group on alanine (from muscle)

Answer 7

Transferred to a-KG to make glutamate

Now alanine = pyruvate

Question 8

Glutamine (from muscle and other tissues) —> …

Answer 8

Glutamine —> glutamate (donates NH4 to urea)

Then…

Glutamate —> a-KG (donates another NH4)

**both are examples of NON-transamination reactions

Question 9

Cahill Glucose-Alanine Cycle

Answer 9

MUSCLE:

Protein —> Glu —> a-KG (and pyruvate —> Alanine)

LIVER:

Alanine and a-KG undergo transamination reaction
—> glutamate donates NH4
—> pyruvate —> gluconeogenesis —> glucose goes back to muscles to complete cycle

Question 10

Alanine transaminase (ALT)

Answer 10

Enzyme for the transamination reaction between

Pyruvate/alanine & glutamate/a-KG

Occurs in muscle and liver in the Cahill glucose-alanine cycle

Question 11

Ketogenic vs. glucogenic amino acids

Answer 11

Glucogenic = can be converted into glucose

Ketogenic = used to make FAs and ketone bodies

Question 12

Cori Cycle

Answer 12

Uses muscle lactate (NOT alanine) to generate glucose

Lactate travels to the liver in the blood

Question 13

Mitochondrial matrix

Regarding the urea cycle

Answer 13

Location for the input of most of the energy (in form of ATP)

Also this is the compartment where regulation occurs

Question 14

Cytosol (urea cycle)

Answer 14

Where bulk of the reactions occur

Where urea is produced and then excreted in the urine

Question 15

Production of carbomyl phosphate

Answer 15

MATRIX

NH4+ (from glutamate)

Combines with CO2 (from bicarbonate)

—> carbomyl phosphate = the activated molecule that enters the urea cycle

ENZYME: carbamoyl phosphate synthetase I (CPS I)

Uses 2 ATP

Question 16

CPS I deficiency

Answer 16

Hyperammonemia

Seizures

Coma

Early death

Question 17

Synthesis of citrulline

Answer 17

MATRIX

Carbamoyl phosphate condenses with ornithine

—> citrulline (releasing an inorganic phosphate)

ENZYME: ornithine transcarbamoylase

Citrulline then enters the cytosol

Question 18

Ornithine transcarbamoylase (OT) deficiency

Answer 18

Hyperammonemia

If severe = coma and death

Signs = decrease citrulline and arginine concentrations

Increase of orotic acid in urine

Question 19

Ornithine is analogous to what molecule in the CAC

Answer 19

OAA

Both are recycled at the end of the cycle

Question 20

Synthesis of argininosuccinate

Answer 20

CYTOSOL

Aspartate condenses with citrulline

ENZYME: argininosuccinate synthetase

Question 21

Argininosuccinate synthetase deficiency

Answer 21

Hyperammonemia

Citrullinemia

Common neurologic complications typicals of UCDs

Question 22

Structural significance of argininosuccinate

Answer 22

(Fumarate)+(urea)+(ornithine)

Question 23

Aspartate transaminase (AST)

Answer 23

Transamination reaction between

Glu/a-KG

Asp/OAA

Question 24

Liver panel enzymes

Answer 24

AST and ALT

If activity is elevated = liver damage

Question 25

Argininosuccinatase

Answer 25

Cleaves argininosuccinate into

Fumarate —> CAC

And

Arginine —> continues in urea cycle

Question 26

Argininosuccinatase deficiency

Answer 26

Hyperammonemia

Argininosuccinate acidemia

Seizures

Common neuro shit for UCDs

Question 27

Arginase

Answer 27

Cleaves arginine into UREA and ornithine

Urea —> excreted in urine

Ornithine —> re-enters the mitochondrial matrix to do another round of urea cycle

Question 28

Arginase deficiency

Answer 28

Hyper-NH4

Argininemia

Slow growth

Mental retardation

Question 29

N-acetylglutamate synthase

Answer 29

Condenses acetyl-CoA and glutamate —> N-acetylglutamate

Allosterically activated by ARGININE

N-acetylglutamate is an allosteric activator of CPS1 (produces carbamoyl phosphate)

Question 30

Excess of glutamate and arginine (and other amino acids) —>

Answer 30

Stimulates urea cycle

Question 31

N-acetylglutamate synthase deficiency

Answer 31

Hyper-NH4

Developmental delay

Mental retard

Seizures

Coma

Death

Question 32

Hep A clinical presentation

Answer 32

Fatigue, loss of appetite, nausea, vomiting, pain in joints

Tender, enlarged liver

LAB = elevation in AST and ALT activity

Symptoms can worsen to neuro problems (toxicity levels of NH4…and liver damage is preventing urea production to get rid of NH4)

Question 33

Hyperammonemia

Answer 33

Inability of the urea cycle to properly function

—> gradual decrease in CAC intermediates (a-KG, OAA, fumarate)

Which affects ATP production in the CNS

Question 34

Lactulose

Answer 34

Medication to reduce NH4 levels

= nondigestible synthetic fructose-Gal disaccharide

Intestinal flora metabolize it to produce lactic and acetic acid —> acidifies colon

—> NH3 —> NH4 which isn’t absorbed as well

Reduces plasma NH4 levels

Question 35

Benzoate and phenylbutyrate

Answer 35

Meds to reduce NH4

Benzoate metabolism uses glycine

Phenylbutyrate uses glutamine

Removes these amino acids from circulation

Cells then need to replace them with biosynthetic pathways…lowers nitrogen load