Lecture 3 - Phenylalanine Degradation

Question 1

Phenylalanine degradation

Answer 1

6 steps

Question 2

Phenylalannine degradation overall process

Answer 2

1. forming tyrosine
2. aminotransferase step
3. forming homogentisate
4. add O2
5. isomerization
6. add water and split

Question 3

1. Forming tyrosine

Answer 3

phenylalanine + tetrahydrobiopterin + O2

–>

tyrosine + dihydrobiopterin + H2O

• phenylalanine = ring
• tetrahydrobiopterin = hydroxylation of aromatic rings
• note - now also TYROSINE DEGRADATION (5 steps)
• phenylalanine hydroxylase

Question 4

2. Aminotransferase step

Answer 4

tyrosine + α-ketoglutarate

–>

p-Hydroxyphenylpyruvate + glutamate

• a priming reaction for many amino acid breakdowns
• glutamate goes on = side product
• removal of α-amino group = urea cycle

Question 5

3. Forming homogentisate

Answer 5

p-hydroxyphenylpyruvate + ascorbate + O2

–>

homogentisate + dihydroascorbate + H2O + CO2

• oxidation reaction • second hydroxyl (OH) added to ring

Question 6

4. Adding O2

Answer 6

homogenitsate + O2

–>

4-maleylacetoacetate

breaks ring, now linear with 4 oxygens

Question 7

5. Isomerisation

Answer 7

4-maleylacetoacetate

–>

4-fumarylacetoacetate

• 4-fumarylacetoacetate is less stable/more active
• can be broken down/acted upon

Question 8

6. Add water and split

Answer 8

4-fumarylacetoacetate + H2O

–>

fumarate + acetoacetate

• fumarate = glucogenic body, good leading group, citric acid cycle
• acetoacetate = ketogenic body, related to citric acid cycle

Question 9

The NIH shift

Answer 9

in creating tyrosine,

the H on C4 position of the ring

shifts to the C3 position

Question 10

NIH shift steps

Answer 10

1. O2 added forms an epoxide ring group
2. this then opens –> forms a carbocation at C3 (unstable)
3. hydride migrates from C4 to C3

• stable carbocation now formed –> oxonium ion
• proton lost –> tyrosine formed • also happens in step 3

Question 11

Diseases

Answer 11

• alkaptonuria
• phenylketonuria

Question 12

Alkaptonuria

Answer 12

• no step 4 (adding O2 to homogentisate)
• deficient homogentisate dioxygenase (enzyme doesn’t function properly)
• build up of homogentisate –> stops process
• excreted in urine
• mild disease, arthritis later in life (pathway not in isolation)

Question 13

Phenylketonuria

Answer 13

• no first step (phenylalanine –> tyrosine)
• can’t make tyrosine because no functioning phenylalanine hydroxylase
• buildup/increased phenylalanine
• reduced tyrosine (only from diet)
• severe mental retardation from early age phenylalanine

–> phenylpyruvate (smells)

Question 14

Phenylalanine degradation

Answer 14