Pyruvate Dehydrogenase Flashcards

1
Q

What does PDH stand for?

(In the context of enzymes)

A

Pyruvate dehydrogenase

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2
Q

What role does the PDH complex serve?

(In an overall sense)

A

It act as a link between glycolysis and the TCA cycle by converting pyruvate into acetyl-CoA so that it may pass into the mitochondrial matrix and feed into the cycle.

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3
Q

Identify:

The specific overall reaction carried out by PDH.

A

Oxidative decarboxylation of pyruvate to form acetyl-CoA.

This generates an NADH as well. (2 NADH overall, as left with 2 pyruvate at the end of glycolysis).

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4
Q

List:

The THREE enzymes that make up the pyruvate dehydrogenase (PDH) complex.

A
  • E1: Pyruvate dehydrogenase.
  • E2: dihydrolipoyl transacetylase.
  • E3: dihydrolipoyl dehydrogenase.
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5
Q

Which binding domains (BD) comprise the pivot point for the lipoyl domain (LpD) ‘swinging arms’?

A

E1BD & E3BD

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6
Q

How many reactions and coenzymes contribute to the oxidative decarboxylation of pyruvate by the PDH complex?

A

Five reactions and coenzymes.

Note: CoA-SH and NAD+ act as substrates too.

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7
Q

Describe:

The ΔG°’ of the PDH catalysed reaction, and what this indicates.

A

It is large and negative, indicating that it is spontaneous and irresversible.

Specifically, it is -33.4 kJ mol-1.

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8
Q

List:

The FIVE coenzymes of the PDH complex.

A
  • TPP (thiamine pyrophosphate; from vitamin B1)
  • Lipoic acid
  • CoA (coenzyme A; from vitamin B5)
  • FAD (flavin adenine dinucleotide; from vitamin B2)
  • NAD+ (nicotinamide adenine dinucleotide; from vitamin B3)
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9
Q

What is the role of the LpD (lipoyl domain) ‘swinging arms’ in the PDH complex?

A

To deliver electrons and intermediates from one active site to another.

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10
Q

What part of the PDH complex is the coenzyme TPP bound to, and by what kind of interaction?

A

Non-covalently bound to E1.

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11
Q

What part of the PDH complex is the coenzyme lipoic acid bound to, and by what kind of interaction?

A

Covalently bound to a Lys on E2.

This forms a lipoamide.

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12
Q

What part of the PDH complex is the coenzyme CoA bound to, and by what kind of interaction?

A

Non-covalently bound to E2.

It is a substrate of E2 and forms part of the product (acetyl-CoA) of the PDH complex.

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13
Q

What part of the PDH complex is the coenzyme FAD bound to, and by what kind of interaction?

A

Covalently bound to E3.

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14
Q

What part of the PDH complex is the coenzyme **NAD+** bound to, and by what kind of interaction?

A

Non-covalently bound to E3.

It is a substrate of E3, and is converted to NADH.

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15
Q

Why can thiamine deficiency lead to severe neurological symptoms?

A

The brain exclusively utilises aerobic respiration to generate energy.

Thiamine is not stored nor synthesised well in most vertebrates, and so must be obtained via diet.

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16
Q

What disease is caused by chronic thiamine deficiency?

A

Beri Beri disease

Main symptoms include neurological dysfunction, paralysis, limb atrophy, and cardiac failure.

17
Q

What happens when lipoic acid binds with Lys on E2 and E3BP?

A

It forms a long lipoamide arm that can swing between the active sites of E1, E2, and E3.

18
Q

What is unique or important about the disulfide bond of the lipoamide arm?

A

It may be reduced to a dithiol group, which can then act as an electron carrier or acyl carrier.

It undergoes redox reactions for these roles.

19
Q

How does arsenic alloesterically inhibit the PDH complex?

A

It readily and irreversibly binds to the dithiol group of the lipoamide arms.

20
Q

What is important about the thiol group of CoA?

(Thiol = a carbon-bonded sulfhydryl ; C-SH)

A

It can covalently bind with an acyl group to form a thioester bond.

This has a high hydrolysis potential (i.e. large negative ΔG), and essentially ‘activates’ the molecule with the acyl group.

An example is acetyl-CoA.

21
Q

What acts as the electron acceptor in the E3 reaction of the PDH complex?

22
Q

Define:

Prosthetic group

(in the context of enzymes)

A

A non-amino acid component that covalently binds to enzymes and assists in their function.

For example, FAD covalently binds to E3 of the PDH complex.

23
Q

Identify:

The enzyme(s), substrate, end product, and any other important byproducts/reactants of the PDH complex reaction I.

A
  • E1: Pyruvate dehydrogenase
  • Decarboxylation of pyruvate to a 2C acetyl group.
  • Binding of this acetyl group to TPP to form a reactive hydroxyethyl-TPP.

Note: TPP first binds to E1 before reacting with the pyruvate.

CO2 is the byproduct of this step.

24
Q

Identify:

The enzyme, substrate, end product, and any other important byproducts/reactants of the PDH complex reaction II.

A
  • E1: pyruvate dehydrogenase to E2: dihydrolipoyl transacetylase
  • A redox reaction whereby the hydroxyethyl-TPP of E1 is oxidised as the hydroxethyl is transferred to the lipoamide disulphide arm of E2 (reduction) to form a thioester intermediate (acetyl-dihydrolipoamide).
25
# Identify: The **enzyme**, **substrate**, **end product**, and any other important **byproducts**/**reactants** of the **PDH complex reaction III**.
- **E2**: **dihydrolipoyl transacetylase** - **Acetyl** group **transferred** to **CoA** by E2. - Simultaneously, the **lipoamide** is **reduced** (**dihydrolipoamide**).
26
# Identify: The **enzyme**, **substrate**, **end product**, and any other important **byproducts**/**reactants** of the **PDH complex reaction IV**.
- **E2**: **dihydrolipoyl transacetylase** to **E3**: **dihydrolipoyl dehydrogenase** - **Redox** reaction where the **dihydrolipoamide** arm is **oxidised** by **reducing** the **FAD** prosthetic group of E3. ## Footnote **Note**: in this step, the **hydrides** attached to FAD are then transferred to the **disulfide** of the **E3** dihydrolipoyl (thus **reducing** it). This is the **disulfide interchange**.
27
# Identify: The **enzyme**, **substrate**, **end product**, and any other important **byproducts**/**reactants** of the **PDH complex reaction V**.
- **E3**: **dihydrolipoyl dehydrogenase** - **NAD+** is **reduced** by **FADH2** after it has **reoxidised** the **disulfide** of E3. ## Footnote In this **FAD** is an important **intermediate**.
28
What is the **disulfide interchange** during **step IV** of the **PDH** reaction complex?
When the **FADH2** passes its two **hydrides** to the **disulfide** of the **E3 dihydrolipoyl** temporarily.
29
What are the **starting substrates** and **end products** of the **PDH** complex reaction? ## Footnote Also known as the **transition** or **prepatory** stage for the TCA cycle.
- **SS**: 2 pyruvate + 2 CoA-SH + 2 NAD+ - **EP**: 2 acetyl-CoA + 2 NADH ## Footnote **Note**: **TPP**, **FAD**, and **lipoate** are also vital for the process.
30
# List: FOUR key **advantages** of **multi-complex enzymes**. ## Footnote (Like the **PDH** complex)
- **Higher reaction rate**. - Reduction of **diffusion dependency**. - Reduced **side reactions**. - **Multiple regulation sites** + **coordinated regulation**.