Lecture 3 - Methionine Degradation

Question 1

Methionine degradation

Answer 1

9 steps

Question 2

Methionine degradation overall process

Answer 2

1. forming SAM
2. methylating an acceptor
3. to homocysteine
4. add serine
5. creating cysteine
6. add CoA
7. add CO2
8. racemisation
9. internal rearrangement

Question 3

1. Forming SAM

Answer 3

methionine + ATP

–>

S-adenosylmethionine + Pi + PPi

• activated methyl cycle = methionine regenerated
• SAM contains highly reactive sulfur ion
• important methylating agent (activation, donates methyl group)

Question 4

2. Methylating an acceptor

Answer 4

SAM + methyl acceptor

–>

S-adenosylhomocysteine + methylated acceptor

Question 5

3. To homocysteine

Answer 5

S-adenosylhomocysteine + H2O

–>

homocysteine + adenosine

Question 6

4. Add serine

Answer 6

homocysteine + serine

–>

cystanthionine + H2O

• adding serine often precursor to another molecule
• serine onto surface of side chain

Question 7

5. Creating cysteine

Answer 7

cystanthionine + H2O

–>

α-ketoglutarate + NH3 + cysteine

• serine backbone + sulfur = cysteine

(side product, increase in concentration of cysteine)

• catabolic breakdown of one amino acid to make a new one

Question 8

6. Add CoA (coenzyme A)

Answer 8

α-ketoglutarate + CoASH + NAD+

–>

propionyl CoA + NADH + CO2

• oxidized α-ketoglutarate –> reduced
• propionyl CoA is also a product of odd-chain fatty acid degradation
• associated not just with methionine but also breakdown of odd chain fatty acids

Question 9

Propionyl CoA is also a product of

Answer 9

odd-chain fatty acid degradation

• associated not just with methionine but also breakdown of odd chain fatty acids

Question 10

7. Add CO2

Answer 10

propionyl CoA + CO2 + ATP

–>

S-methylmalonyl CoA + ADP + Pi

• S-methylmalonyl CoA has “handedness”
• activating requires activation of propionyl CoA
• uses biotin prosthetic group for CO2 transfer

Question 11

8. Racemisation (L –> R)

Answer 11

S-methylmalonyl CoA

<==>

R-methylmalonyl CoA

• R form used in subsequent reactions

Question 12

9. Internal rearrangement

Answer 12

R-methylmalonyl CoA

–>

succinyl CoA

• right form –> succinyl CoA which is more stable with the same number of carbons
• enzyme = methylmalonyl CoA mutase, contains coenzyme B12

Question 13

Diseases

Answer 13

methylmalonic acidemia

Question 14

Methylmalonic acidemia

Answer 14

• a group of related diseases centered on methylmalonyl CoA mutase
• severity and onset depend on the degree of enzyme mutation
• buildup of methylmalonic acid and byproducts in body fluids (dependent on concentration of byproducts) - methyl citrate -propionic acid - 3-OH propionic acid - carnitine levels low

Question 15

Treatment of methylmalonic acidemia

Answer 15

• type-dependent
• carnitine intake
• cobalamin intake
• liver transplant

Question 16

Methionine degradation

picture

Answer 16