Pyruvate Dehydrogenase

Question 1

Via what channels does pyruvate enter the inner area of the mitochondria?

Answer 1

• Outer membrane: Voltage-gated porin complex

- Inner: Mitochondrial pyruvate carrier (MPC)

Question 2

What is the enzyme which turns pyruvate towards gluconeogenesis in the mitochondria?

Answer 2

Pyruvate Carboxylase

Question 3

What is the enzyme which turns pyruvate into Acetyl-Coa?

Answer 3

Pyruvate dehydrogenase complex

Question 4

What molecule can slow down the TCA cycle and increase the levels of acetyl coa?

Answer 4

ATP

Question 5

What enzyme does Acetyl Coa activate?

Answer 5

Pyruvate carboxylase

Question 6

What are the 3 enzymes which make up the pyruvate dehydrogenase complex?

Answer 6

• Pyruvate dehydrogenase (E1)
• Dihydrolipoyl transacetylase (E2)
• Dihydrolipoyl dehydrogenase (E3)

Question 7

What are the 5 co-factors required by the pyruvate dehydrogenase complex?

Answer 7

• NAD+
• FAD+
• Coenzyme A (coA)
• Thiamine
• Lipoic acid

Question 8

What is the role of E1 (Pyruvate dehydrogenase)?

Answer 8

Converts:

• Pyruvate
• Thiamine-PP

into:

• CO2
• Thiamine skeleton of pyruvate on to thiamine PP

Question 9

What is the role of E2 (Dihydrolipoyl transacetylase)?

Answer 9

Thimaine pyrophosphate carbon complex combined with lipoic acid to create:

• Carbon skeleton attached to lipoic acid

Question 10

What is added to the Carbon skeleton attached to lipoic acid to make acetyl coA?

Answer 10

CoA

Question 11

What is the function of E3 (Dihydrolipoyl dehydrogenase)?

Answer 11

Uses NAD and FAD+ cofactors to keep lipoic acid in proper form to be used by E2 subunit

Question 12

What is the active form of thiamine (B1)?

Answer 12

Thiamine pyrophosphate (TPP)

Question 13

What 4 enzymes is TPP a cofactor for?

Answer 13

• Pyruvate dehydrogenase
• Alpha-ketoglutarate dehydrogenase (TCA cycle)
• Alpha-ketoacid dehydrogenase (branched chain amino acids)
• Transkelotase (HMP shunt)

Question 14

Thiamine deficiency results in a decreased production of what molecule?

Answer 14

ATP

Question 15

What tissues are most affected by decreased ATP (as a result of thiamine deficiency)?

Answer 15

Aerobic tissues (nerves/heart)

Question 16

What groups get beriberi syndrome?

Answer 16

Underdeveloped areas children

Question 17

What are the symptoms of dry beriberi?

Answer 17

• Polyneuritis

- Muscle weakness

Question 18

What are the symptoms wet beriberi?

Answer 18

• Tachycardia
• high-output HF
• Edema

Question 19

What are some symptoms of Wernicke-Korsakoff syndrome?

Answer 19

• Confusion

- Confabulation

Question 20

What happens if you give malnourished (e.g alcoholic) patients glucose without thiamine?

Answer 20

If thiamine deficient they will get worsened Wernicke-Korsakoff syndrome
- Will be unable to metabolise glucose

Question 21

What is FAD+ synthesised from?

Answer 21

B2 - Riboflavin

Question 22

What does adenosine + riboflavin give?

Answer 22

FAD+

Question 23

What does FAD+ become when given 2 electrons?

Answer 23

FADH2

Question 24

What is NAD+ synthesised from?

Answer 24

Niacin (B3)

Question 25

What is niacin synthesised from?

Answer 25

Tryptophan

Question 26

What does NAD+ carry electrons as?

Answer 26

NADH

Question 27

What is NAD+ useful for?

Answer 27

Electron transport

Question 28

What is coenzyme A synthesised from?

Answer 28

Pantothenic acid (B5)

Question 29

What does coenzyme A accept and donate?

Answer 29

Acyl groups

Question 30

What does lipoic acid bond with to create?

Answer 30

Bonds with lysine to create lipoamide

Question 31

What does lipoic acid act as a co-factor for?

Answer 31

E2

Question 32

What is lipoic acid inhibited by?

Answer 32

Arsenic

Question 33

How does arsenic inhibit lipoic acid to cause disease?

Answer 33

- Binds to lipoic acid | - Inhibits PDH (like thiamine deficiency)

Question 34

What causes arsenic poisoning to create a garlic like breath?

Answer 34

Oxidised to arsenois oxide which smells like garlic

Question 35

What are some of the non-specific symptoms of arsenic poisoning

Answer 35

- Vomitting, diarrhea - Coma - Death

Question 36

How is PDH made inactive?

Answer 36

Through phsophorylation by PDH kinase

Question 37

How is PDH made active?

Answer 37

Through dephosphorylation by PDH phosphatase

Question 38

What substances activate PDH?

Answer 38

- NAD (incr ratio to NADH) - ADP - Ca2+

Question 39

What substances inactivate PDH?

Answer 39

- NADH (decreased ratio of NAD to NADH) - ACoA - ATP

Question 40

How is PDH complex deficiency inherited?

Answer 40

- X-linked usually | - Most commonly due to mutations in PDHA1 gene

Question 41

What part of the pyruvate dehydrogenase complex is affected in PDH complex deficiency?

Answer 41

E1-alpha subunit

Question 42

What metabolic issue do babies with PDH complex deficiency present with?

Answer 42

Lactic acidosis

Question 43

What are the key findings / symptoms of a baby with PDH complex deficiency?

Answer 43

- Poor feeding, growth failure, developmental delay - Elevated alanine - Lactic acidosis

Question 44

What are examples of mitochondrial disorders whoch all cause lacic acidosis?

Answer 44

- Pyruvate dehydrogenase complex deficiency - Pyruvate carboxylase deficiency - Cytochrome oxidase deficiencies

Question 45

How is PDH complex deficiency treated?

Answer 45

Supplement: - Thiamine - Lipoic acid Ketogenic diet: - Low carb (reduces lactic acidosis) - High fat - Ketogenic amino acis: Lysine and leucine - Drives ketone production (instead of glucose)

Question 46

What 2 substances are lysine and leucine converted to?

Answer 46

Acetoacetate Acetyl CoA - Straight into TCA cycle - Cannot be used for gluconeogensis and back into pyruvate (worsening lactic acidosis)