Pyruvate dehydrogenase complex

Pyruvate dehydrogenase complex (PDC) role

Links glycolysis to the citric acid cycle by converting pyruvate to acetyl-CoA

Critical regulatory point

PDC reaction is irreversible and controls entry of carbon into the citric acid cycle

Glucose importance

Primary fuel for most organisms

Brain fuel

Glucose is the main fuel under non-starving conditions

Red blood cell fuel

Glucose is the only fuel used

Alternative fuels

Fatty acids and amino acids can also be oxidised for energy

Fuel degradation outcome

Produces NADH, FADH₂, CO₂, and small amounts of ATP/GTP

Cellular respiration

Process of extracting high-energy electrons from fuels to generate ATP

Oxidative metabolism

Oxygen-dependent processes converting nutrients into ATP

Citric acid cycle role in respiration

Removes high-energy electrons as NADH and FADH₂

Electron transport chain role

Uses electrons to reduce O₂ and generate proton gradient

Oxidative phosphorylation

ATP synthesis driven by electron transport and oxygen reduction

Oxidative decarboxylation

Removal of CO₂ combined with oxidation of substrate

Acyl group transfer

Movement of an acyl group between molecules

Thioester bond

High-energy bond between acyl group and sulphur atom

Cofactors

Molecules required for enzyme activity (e.g. TPP, lipoamide, FAD, NAD⁺, CoA)

Pyruvate origin

Produced from glucose during glycolysis

Aerobic condition requirement

Oxygen required for pyruvate to enter mitochondria

Mitochondrial pyruvate carrier (MPC)

Transports pyruvate into mitochondria

MPC structure

Composed of MPC1 and MPC2 subunits

PDC location

Mitochondrial matrix

Mitochondrial structure

Double membrane with inner folds called cristae

Endosymbiotic origin

Mitochondria evolved from aerobic bacteria

PDC composition

Three enzymes (E1, E2, E3) forming a multi-enzyme complex

PDC overall reaction

Pyruvate + CoA + NAD⁺ → acetyl-CoA + CO₂ + NADH + H⁺

Acetyl-CoA structure

Acetyl group linked to CoA via thioester bond

Coenzyme A composition

Contains ADP, pantothenic acid (vitamin B5), and cysteamine

PDC cofactors

Five required cofactors for activity

Catalytic cofactors

TPP, lipoic acid, FAD (regenerated during reaction)

Stoichiometric cofactors

CoA and NAD⁺ (consumed in reaction)

PDC reaction steps

Decarboxylation, oxidation, acetyl transfer, and cofactor regeneration

Energy coupling

Decarboxylation energy drives NADH and acetyl-CoA formation

E1 function

Decarboxylates pyruvate to form hydroxyethyl-TPP

E2 function

Transfers acetyl group via lipoamide arm to CoA

E3 function

Regenerates oxidised cofactors and produces NADH

Lipoamide arm

Flexible group that transfers intermediates between active sites

Acetyl-lipoamide

Intermediate carrying acetyl group during reaction

FAD role in PDC

Accepts electrons from reduced lipoamide

NAD⁺ role in PDC

Final electron acceptor forming NADH

Acetyl-CoA fate

Enters citric acid cycle for complete oxidation to CO₂

CAC electron harvesting

Generates NADH and FADH₂ for ATP production

CAC carbon flow

Acetyl (2C) + oxaloacetate (4C) → citrate (6C)

CO₂ release in CAC

Two carbons released per cycle

ATP production in CAC

One ATP (or GTP) per cycle

Low ATP yield in CAC

Cycle mainly produces electron carriers rather than ATP

Oxygen use in CAC

Does not directly use oxygen

PDC allosteric regulation

Controlled by product and energy levels

Acetyl-CoA inhibition

Inhibits E2 component

NADH inhibition

Inhibits E3 component

PDC phosphorylation regulation

Activity controlled by phosphorylation state

PDK (kinase)

Phosphorylates E1 and inactivates PDC

PDP (phosphatase)

Dephosphorylates E1 and activates PDC

Energy charge regulation

PDC responds to ATP/ADP and NADH/NAD⁺ ratios

High energy state

High ATP, NADH, acetyl-CoA promote PDC inhibition

Low energy state

High ADP and pyruvate promote PDC activation

Calcium regulation

Ca²⁺ activates phosphatase to stimulate PDC activity

Exercise response

Increased Ca²⁺ and ADP activate PDC in muscle

Hormonal regulation of PDC

Controlled by hormones in specific tissues

Epinephrine effect

Increases Ca²⁺ to activate PDC in liver

Insulin effect

Activates phosphatase, promoting acetyl-CoA production

Resting conditions

High energy ratios activate PDK and inhibit PDC

Active conditions

Increased demand inhibits PDK and activates PDC

PDC phosphatase deficiency

Causes constant inactivation of PDC

Metabolic consequence

Pyruvate converted to lactate instead of acetyl-CoA

Lactic acidosis

Accumulation of lactate leading to acidic conditions

Diabetic neuropathy

Nerve damage causing pain and numbness

Hyperglycaemia effect

Increases PDK activity, inhibiting PDC

Lactate accumulation

Leads to activation of pain receptors

Neuropathy mechanism

Excess lactate stimulates acid-sensing nociceptors