L10 - The Pyruvate Dehydrogenase Complex

Once pyruvate is generated from glycolysis, it's going to be moved to the matrix of the mitochondria via

a mitochondrial pyruvate carrier to be processed further by the pyruvate dehydrogenase complex

How is pyruvate processed under anaerobic conditions? Why is this necessary?

Under hypoxic/anaerobic conditions, pyruvate accumulates, and there’s a low level of NAD⁺ necessary to continue glycolysis. Lactate/ethanol fermentation solves this issue by processing pyruvate into lactate or ethanol and CO_2, and producing NAD⁺; this allows glycolysis to continue

Lactate dehydrogenase

Pyruvate + NADH + H⁺ → L-Lactate + NAD⁺; certain parts of the body produces lactase for certain processes

The Warburg Effect

The observation that tumor cells have high rates of glycolysis, with fermentation of glucose to lactate, even in the presence of oxygen - basis of PET scans to diagnose tumors

Pyruvate Dehydrogenase Complex (PDH); Basic information

Function: Processes pyruvate into Acetyl-CoA and CO₂ (First CO₂ releasing process)

Three main enzymes: E_1, E_2, and E₃

Also contains regulatory kinase and phosphatase; Each complex contains several subunits of the E complex; Overall reaction is a large -ΔG

E₁ name, function, and cofactor information

• Pyruvate Dehydrogenase: Pyruvate goes through decarboxylation reaction, releasing CO₂ and generating Hydroxyethyl TPP

• Cofactors - Thiamine pyrophosphate (TPP)

  • From Thiamine/Vitamin B1; Contains C-H group on thiazolium ring that participates in E reaction

E₂ name, function, and cofactor information

• Dihydrolipoyl transacetylase: Oxidized lipoyllysine (on E₂) takes the hydroxyethyl group from TPP and reduces it to form acyl lipoyllysine (Thiol ester). The acetyl structure is then transferred onto CoA-SH to form Acetyl-CoA. Leaves lipoyllysine in reduced state.

• Cofactor - Coenzyme A (CoA-SH) and Lipoic acid (lipoate)

  • CoA-SH: From pantothenic acid/Vitamin B5; Contains a reactive thiol group (thiazolium ring) that forms a thioester with acetate to produce acetyl-CoA; written as CoA-SH to show it hasn’t yet formed a thioester bond

  • Lipoate: Provides reactive disulfide that can participate in reaction; Bound to Lys in E₂; Oxidized has ring structure → reduced to two disulfide bonds → acetylated in the E₂ reaction; Is on the enzyme

E₃ name, function, and cofactor information

• Dihydrolipoyl dehydrogenase: Reoxidizes lipoyllysine to restore function via FAD. The FADH₂ formed is reduced using NAD⁺, creating NADH + H⁺

• Cofactor - Flavin adenine dinucleotide (FAD) and NAD⁺

  • FAD: From Riboflavin/Vitamin B2; B2 is also a precursor to flavin mononucleotide (FMN); FAD and FMN both participate in redox reactions; Tightly bound to enzyme so reduction and oxidation occur in the same spot; Can be reduced twice: FAD → FADH (Semiquinone intermediate) → FADH₂

  • NAD⁺: From Niacin/nicotinic acid/vitamin B3; Accepts 2H at once: NAD⁺ → NADH (no intermediate); mobile electron carrier

Inhibitors and Activators of PDH complex

Inhibited by ATP (PDK) and products of enzyme (Acetyl-CoA and NADH)

Activated by AMP (PDP), CoA-SH, and NAD⁺

NADP+ is phosphorylated form of

NAD+

PDH is located in the

mitochondria

___ inactivates PDH

PDK (Pyruvate dehydrogenase kinase); Regulated by high ATP

___ activates PDH

PDP (Pyruvate dehydrogenase phosphatase); Activated by high AMP

Insulin signalling will ____ PDP

activate

In high glucose concentration, the liver and adipocytes will do what in relation to PDH

High glucose releases insulin that will cause PDP to activate and use up the high blood glucose

PDP is also activated by what from the muscle

Calcium, signals a need for energy which causes acetyl-CoA production

Glucagon does OR does not impact PDH

DOES NOT