Kiersti's High Yield of Urea Cycle

Question 1

When do we have a positive nitrogen balance? (N intake > N excretion)

Answer 1

• During growth (from infancy to teens, and during pregnancy)
• During recovery from illness or malnutrition

Question 2

When do we have a negative nitrogen balance?

Answer 2

illness

malnutrition

severe burn victims

Question 3

Urea is the main way that nitrogen is excreted. What are the other ways?

Answer 3

NH4+

Creatinine

Uric Acid

Question 4

What happens to BUN, Blood creatinine levels, and blood uric acid levels during pregnancy?

Answer 4

They all DECREASE!

(Note that during pregancy GFR increases)

Question 5

BUN increases in………………. damage and decreases during………….. damage.

Answer 5

kidney

liver

Question 6

What are the main steps in amino acid degredation?

Answer 6

• Removal of nitrogen
• Clearance of NH4+ (urea cycle)
• Utilization of the carbon backbone

Question 7

What are the 3 types of reactions to remove nitrogen from amino acids?

Answer 7

Transamination (main way!)

deamination

deamidation

Question 8

Deamination is the removal of the alpha amino group of certain amino acids as NH4+. These amino acids are….

Answer 8

Glutamate ***

Glycine

Serine

Threonine

Histidine

Question 9

Deamidation is the removal of an amide group as NH4+ from which amino acids?

This provides most of the NH4+ in the urine. It is most important in which organ?

Answer 9

Glutamine and asparagine

Kidney

Question 10

Transamination reactions are reversible! The amino nitrogen is generally collected on what?

Answer 10

Glutamate!

Question 11

What is the coenzyme for transamination reactions?

Answer 11

Pyridoxal phosphate (PLP)

Question 12

Which aminotransferase/Transaminase is more specific, ALT or AST?

Answer 12

ALT

Question 13

Glutamate plays a central role in nitrogen removal. How?

Answer 13

• it collects nitrogen via transamination
• provides NH4+ to the urea cycle both directly and indirectly
• Its a precursor for N-acetyl glutamate (the allosteric activator of the urea cycle)

Question 14

How does glutamate provide NH4+ to the urea cycle directly?

Answer 14

via deamination by glutamate dehydrogenase.

Question 15

How does glutamate provide NH4+ to the urea cycle indirectly?

Answer 15

by transaminating oxaloacetate into aspartate (which then can provide an amino group to urea).

Question 16

What are the 2 major mechanisms to control blood ammonia levels?

Answer 16

• Transamination rxns to “collect” nitrogen on glutamate
• “fixing” free ammonia into organic molecules

Question 17

What are the enzymes used for the 3 rxns that “fix” free ammonia into organic molecules?

Answer 17

• Glutamate dehydrogenase
• Glutamine synthetase (main detoxyfication rxn in brain)
• CPSI (1st step in urea synthesis)

Question 19

Glutamine synthetase catalyzes the main detoxification rxn in the brain. What is this rxn?

Answer 19

Glutamate + NH4+ + ATP –> Glutamine

Question 20

Where is the only place the urea cycle takes place?

Answer 20

The liver!

Question 21

How is nitrogen carried to the liver?

Answer 21

Alanine and glutamine

Question 22

The transport of alanine to the liver serves what 2 main purposes?

Answer 22

1. Removal of nitrogen through the urea cycle
2. Gluconeogenesis

Question 23

The main sources of alanine is the muscle. What are the other sources?

Answer 23

Kidney and intestines

* Due to converting glutamine -> alanine

Glutamine -> Glutamate -> alanine

Question 24

Glutamine -> Glutamate -> alanine

What enzyme makes glutamine into glutamate?

What makes glutamate into alanine?

Answer 24

glutaminase

ALT

Question 25

Which organs are the main glutamine **producers**?

Answer 25

**Muscle** and **brain**

Question 26

Which organs are the main glutamine **users**?

Answer 26

**Kidney, gut, immune cells** and **liver**

Question 27

What enzyme catalyzes the **rate limiting step** in the urea cycle?

Answer 27

CPSI

Question 28

What is the allosteric activator of CPSI?

Answer 28

**N-Acetyl Glutamate** \* Note that **Arginine** is the allosteric activator for the enzyme that makes N-Acetyl Glutamate!

Question 29

Which urea cycle intermediate enters the TCA cycle to regenerate **oxaloacetate** and then **aspartate**?

Answer 29

Fumarate

Question 30

Which urea cycle intermediate leaves the mitochondria?

Answer 30

Citrulline

Question 31

Will nitrogen excretion increase or decrease during fasting and starvation?

Answer 31

During _fasting,_ nitrogen excretion will increase as the body degrades muscle to amino acids, to transport to the liver to make glucose. Then during _starvation_, levels will fall as the brain switches from glucose to ketone bodies! (so muscle degredation decreases)

Question 32

What results from **hyperammonemia**?

Answer 32

**hepatic encephalopathy,** cerebral edema, seizures, nausea, vomiting, lethargy, death.

Question 33

**Primary hyperammonemias** are due to what?

Answer 33

Defective enzymes!

Question 34

**Secondary hyperammonemias** are due to what?

Answer 34

Mainly from **hepatic failure**, meaning that hepatocytes can't carry out the urea cycle. Also can be caused by genetic defects not related to urea cycle enzymes.

Question 35

All primary hyperammonemias are **autosomal recessive**, _except_ which one?

Answer 35

Type II hyperammonemia (OTC) which is **X-Linked recessive**

Question 36

Type II hyperammonemia (due to the defective OTC enzyme) leads to a build up of **carbamoyl phosphate**. When this occurs, it goes to the cytoplasm to be made into what?

Answer 36

**Orotate** \* orotate levels will be increased in urine!

Question 37

To manage urea cycle disorders, the patient should reduce the ammonia load on the urea cycle by a l**ow protein diet**, **avoiding fasting**, and **taking scavenger drugs**. What are the scavenger drugs we need to know?

Answer 37

**Benzoate** and **Phenylbutyrate** \* Scavenger drugs conjugate amino acids and target them for urinary excretion!

Question 38

Patients with urea cycle disorders should be provided with what urea cycle intermediates?

Answer 38

- **Arginine** (if arginosuccinate lyase is deficient. It will generate more ornithine for the cycle to continue) - **Citrulline** (in type I and II hyperammonemia. It captures aspartate, so at least one nitrogen can be excreted)