Pyruvate Dehydrogenase (PDH) Complex & Tricarboxylic Acid (TCA) Cycle

Pyruvate Dehydrogenase (PDH) Complex Location

Located in the mitochondrial matrix.

Tissues with High PDH Complex Activity

Found in energy-demanding tissues such as muscles, heart, and brain.

Pyruvate dehydrogenase

E1 of the PDH Complex.

Dihydrolipoamide acetyltransferase

E2 of the PDH Complex.

Dihydrolipoamide dehydrogenase

E3 of the PDH Complex.

Cofactors of PDH Complex

T: Thiamine pyrophosphate (TPP), L: Lipoic acid, C: Coenzyme A (CoA), F: Flavin adenine dinucleotide (FAD), N: Nicotinamide adenine dinucleotide (NAD⁺).

Activators of the PDH Complex

Pyruvate, ADP, Calcium (Ca²⁺).

Inhibitors of the PDH Complex

NADH, Acetyl-CoA, ATP.

Role of PDH Kinase

Phosphorylates and inactivates the PDH complex.

Role of PDH Phosphatase

Dephosphorylates and activates the PDH complex.

Symptoms of PDH Deficiency

Developmental delay, seizures, hypotonia, lactic acidosis, neurodegeneration.

Diagnosis of PDH Deficiency

Blood/CSF lactate and pyruvate levels, genetic testing, enzyme activity assays.

Treatment for PDH Deficiency

Ketogenic diet (alternative fuel from ketones), Dichloroacetate (DCA) (activates PDH phosphatase), Thiamine supplementation (for responsive cases).

Reactants of the TCA Cycle

Acetyl-CoA + Oxaloacetate → Citrate.

Products of the TCA Cycle (per Acetyl-CoA)

2 CO₂, 3 NADH, 1 FADH₂, 1 GTP (or ATP).

ATP Yield from One Acetyl-CoA in the TCA Cycle

10 ATP equivalents (7.5 from NADH, 1.5 from FADH₂, 1 from GTP).

Inhibitors of the TCA Cycle

NADH, Succinyl-CoA, Citrate, ATP.

Activators of the TCA Cycle

ADP, Calcium (Ca²⁺).

Role of Calcium (Ca²⁺) in TCA Cycle Regulation

Activates isocitrate dehydrogenase and α-ketoglutarate dehydrogenase.

Function of Citrate Synthase

Converts Acetyl-CoA + Oxaloacetate → Citrate.

Inhibitors of Citrate Synthase

Citrate, ATP, NADH, Succinyl-CoA.

Function of Isocitrate Dehydrogenase

Converts isocitrate → α-ketoglutarate, producing CO₂ and NADH.

Activators of Isocitrate Dehydrogenase

ADP, Calcium (Ca²⁺).

Inhibitors of Isocitrate Dehydrogenase

ATP & NADH.

Function of α-Ketoglutarate Dehydrogenase

Converts α-ketoglutarate → Succinyl-CoA, producing CO₂ and NADH.

Activators of α-Ketoglutarate Dehydrogenase

Calcium (Ca²⁺).

Inhibitors of α-Ketoglutarate Dehydrogenase

NADH & Succinyl-CoA.

Metabolic Role of Succinyl-CoA

Heme synthesis.

Metabolic Role of Oxaloacetate

Gluconeogenesis.

Metabolic Role of α-Ketoglutarate & Oxaloacetate

Amino acid synthesis.

Metabolic Role of Citrate

Fatty acid synthesis.