Pyruvate Dehydrogenase Flashcards
Via what channels does pyruvate enter the inner area of the mitochondria?
- Outer membrane: Voltage-gated porin complex
- Inner: Mitochondrial pyruvate carrier (MPC)
What is the enzyme which turns pyruvate towards gluconeogenesis in the mitochondria?
Pyruvate Carboxylase
What is the enzyme which turns pyruvate into Acetyl-Coa?
Pyruvate dehydrogenase complex
What molecule can slow down the TCA cycle and increase the levels of acetyl coa?
ATP
What enzyme does Acetyl Coa activate?
Pyruvate carboxylase
What are the 3 enzymes which make up the pyruvate dehydrogenase complex?
- Pyruvate dehydrogenase (E1)
- Dihydrolipoyl transacetylase (E2)
- Dihydrolipoyl dehydrogenase (E3)
What are the 5 co-factors required by the pyruvate dehydrogenase complex?
- NAD+
- FAD+
- Coenzyme A (coA)
- Thiamine
- Lipoic acid
What is the role of E1 (Pyruvate dehydrogenase)?
Converts:
- Pyruvate
- Thiamine-PP
into:
- CO2
- Thiamine skeleton of pyruvate on to thiamine PP
What is the role of E2 (Dihydrolipoyl transacetylase)?
Thimaine pyrophosphate carbon complex combined with lipoic acid to create:
- Carbon skeleton attached to lipoic acid
What is added to the Carbon skeleton attached to lipoic acid to make acetyl coA?
CoA
What is the function of E3 (Dihydrolipoyl dehydrogenase)?
Uses NAD and FAD+ cofactors to keep lipoic acid in proper form to be used by E2 subunit
What is the active form of thiamine (B1)?
Thiamine pyrophosphate (TPP)
What 4 enzymes is TPP a cofactor for?
- Pyruvate dehydrogenase
- Alpha-ketoglutarate dehydrogenase (TCA cycle)
- Alpha-ketoacid dehydrogenase (branched chain amino acids)
- Transkelotase (HMP shunt)
Thiamine deficiency results in a decreased production of what molecule?
ATP
What tissues are most affected by decreased ATP (as a result of thiamine deficiency)?
Aerobic tissues (nerves/heart)
What groups get beriberi syndrome?
Underdeveloped areas children
What are the symptoms of dry beriberi?
- Polyneuritis
- Muscle weakness
What are the symptoms wet beriberi?
- Tachycardia
- high-output HF
- Edema
What are some symptoms of Wernicke-Korsakoff syndrome?
- Confusion
- Confabulation
What happens if you give malnourished (e.g alcoholic) patients glucose without thiamine?
If thiamine deficient they will get worsened Wernicke-Korsakoff syndrome
- Will be unable to metabolise glucose
What is FAD+ synthesised from?
B2 - Riboflavin
What does adenosine + riboflavin give?
FAD+
What does FAD+ become when given 2 electrons?
FADH2
What is NAD+ synthesised from?
Niacin (B3)
What is niacin synthesised from?
Tryptophan
What does NAD+ carry electrons as?
NADH
What is NAD+ useful for?
Electron transport
What is coenzyme A synthesised from?
Pantothenic acid (B5)
What does coenzyme A accept and donate?
Acyl groups
What does lipoic acid bond with to create?
Bonds with lysine to create lipoamide
What does lipoic acid act as a co-factor for?
E2
What is lipoic acid inhibited by?
Arsenic
How does arsenic inhibit lipoic acid to cause disease?
- Binds to lipoic acid
- Inhibits PDH (like thiamine deficiency)
What causes arsenic poisoning to create a garlic like breath?
Oxidised to arsenois oxide which smells like garlic
What are some of the non-specific symptoms of arsenic poisoning
- Vomitting, diarrhea
- Coma
- Death
How is PDH made inactive?
Through phsophorylation by PDH kinase
How is PDH made active?
Through dephosphorylation by PDH phosphatase
What substances activate PDH?
- NAD (incr ratio to NADH)
- ADP
- Ca2+
What substances inactivate PDH?
- NADH (decreased ratio of NAD to NADH)
- ACoA
- ATP
How is PDH complex deficiency inherited?
- X-linked usually
- Most commonly due to mutations in PDHA1 gene
What part of the pyruvate dehydrogenase complex is affected in PDH complex deficiency?
E1-alpha subunit
What metabolic issue do babies with PDH complex deficiency present with?
Lactic acidosis
What are the key findings / symptoms of a baby with PDH complex deficiency?
- Poor feeding, growth failure, developmental delay
- Elevated alanine
- Lactic acidosis
What are examples of mitochondrial disorders whoch all cause lacic acidosis?
- Pyruvate dehydrogenase complex deficiency
- Pyruvate carboxylase deficiency
- Cytochrome oxidase deficiencies
How is PDH complex deficiency treated?
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)
What 2 substances are lysine and leucine converted to?
Acetoacetate
Acetyl CoA
- Straight into TCA cycle
- Cannot be used for gluconeogensis and back into pyruvate (worsening lactic acidosis)
