Pyruvate Dehydrogenase Complex

What is the function of the pyruvate dehydrogenase complex?

The PDH oxidizes pyruvate into acetyl CoA and CO₂. This reaction generates NADH.

Describe the permeability of the mitochondrial membranes.

The outer membrane contains porins that allow for the free diffusion of most low weight molecules.

The inner membrane is impermeable to most charged molecules.

What enzymes are found in the mitochondrial matrix?

1. PDH complex.

2. CAC enzymes.

3. FA oxidation enzymes.

How does pyruvate enter the mitochondrial matrix? What are the consequences?

Pyruvate is charged, so it cannot diffuse through the inner membrane.

It is transported with an H+ symporter.

Pyruvate transport partially dissipates the H+ gradient formed by the ETC.

Which five vitamins are required by the PDH complex? Where are they found?

1. Niacin/Vitamin B3 - NAD+.

2. Riboflavin/Vitamin B2 - FAD+.

3. Thiamine/Vitamin B1 (active form = TPP) - covalently bound to PDH Complex.

4. Lipoate/Lipoic Acid - conjuaged to PDH Complex with an amide bond.

5. Pantothenic Acid/Vitamin B5 - CoA.

The PDH Complex has ___ subunits and over ___ enzymes.

1. 3: E1, E2, and E3.

2. 30.

The E1 subunit of PDH complex is called ___. What is the function of this subunit?

1. Pyruvate Dehydrogenase.

2. Pyruvate is decarboxylated, and the 2 carbon hydroxy-ethyl group is transferred to TPP forming hydroxyethyl-TPP. The hydroxyethyl group is oxidized to form an acetyl group.

The E2 subunit of PDH complex is called ___. What is the function of this subunit?

1. Dihydrolipoyl Transacetylase.

2. Transfers the acetyl group from TPP to lipoate, reduces lipoate's disulfide bond, and transfers the acetyl group to CoA-SH.

The E3 subunit of PDH complex is called ___. What is the function of this subunit?

1. Dihydrolipoyl Dehydrogenase.

2. Reoxidizes lipoyllysine using electrons form FADH₂. FADH₂ is reduced to FAD, and the electrons are used to generate NADH.

The PDH complex uses three cofactors. What are they, and which subunit are they associated with?

1. TPP is associated with pyruvate dehydrogenase.

2. Lipoate is associated with dihydrolipoyl transacetylase.

3. FAD⁺ is associated with dihydrolipoyl dehydrogenase.

The PDH complex is primarily regulated by ___.

Covalent modification, specifically phosphorylation.

The PDH Kinase phosphorylates and _1_ the PDH complex.

The kinase is activated by _2_, _3_, and _4_.

The kinase is inactivated by _5_.

1. Inactivates.

2. Acetyl CoA.

3. NAD.

4. ADP.

5. Pyruvate.

A phosphatase _1_ the PDH complex.

The phosphatase is activated by _2_.

1. Activates.

2. Ca²⁺.

The PDH complex is also regulated allosterically. Which molecules activate the complex, and which molecules inactivate it?

Activators: CoA, NAD⁺, and AMP.

Inactivators: Acetyl CoA, NADH, ATP, and LCFAs.

Beriberi is usually caused by malnourishment and is the result of what type of deficiency?

Thiamine/Vitamin B1 Deficiency.

TPP is active vitamin B1, and it is necessary for the function of PDH complex. This limits the energy that the PDH can derive from glucose.

What is a common symptom of beriberi? How is beriberi treated?

1. Lactic Acidosis.

2. Treatment includes increased consumption of ketogenic amino acids and fat, which bypass the PDH complex to generate Acetyl CoA.

What complicates beriberi in alcoholics?

Alcoholics generally get sufficient amounts of glucose, so increases in insulin prevent the generation of sufficient ketone bodies to supply fuel to the brain.

What is the molecular mechanism behind arsenate and mercury poisoning?

Arsenate and mercury are heavy metals that bind to -SH groups and can disrupt the function of Lipate in the E2 subunit of the PDH complex. This produces symptoms similar to Beriberi.

What is the molecular defect that results in Leigh's disease? How common is the disease?

1. Molecular defects in the genes encoding PDH complex enzymes, particularly the E1 subunit.

2. It affects 1 in 10,000 live births.

What are the symptoms of Leigh's disease?

1. Hypotonic seizures.

2. Opthalmaloplegia.

3. Ataxia.

4. Lactic acidemia.

5. Subacute necrotizing encephalomyelopathy.

6. Rapid progressive degeneration of the CNS.

7. Symmetrical patches of dying brain cells.