Pyruvate Dehydrogenase Complex & TCA Cycle

Comprehensive vocabulary flashcards covering the pyruvate dehydrogenase complex, the TCA cycle, required cofactors, pathway energetics, and related clinical conditions based on the lecture notes.

Pyruvate Translocase

The specific transport protein in the inner mitochondrial membrane that transports pyruvate from the cytosol into the mitochondrial matrix.

Oxidative Decarboxylation

A reaction type in which a carboxyl group is removed as $\text{CO}_2$ and two electrons are transferred to generate $\text{NADH}$, such as in the conversion of pyruvate to acetyl-CoA.

Pyruvate Dehydrogenase Complex

A mitochondrial matrix multi-enzyme complex containing 3 separate enzymes and requiring 5 coenzymes that catalyzes the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA under aerobic conditions.

Pyruvate Dehydrogenase (E1)

The catalytic component of the PDH complex that decarboxylates pyruvate using thiamine pyrophosphate (TPP) as its required coenzyme.

Dihydrolipoyl Transacetylase (E2)

The enzyme component of the PDH complex that transfers the acetyl group to coenzyme A, requiring lipoic acid and coenzyme A (CoA-SH).

Dihydrolipoyl Dehydrogenase (E3)

The enzyme component of the PDH complex that reoxidizes the reduced lipoic acid cofactor, requiring FAD and $\text{NAD}^+$.

Thiamine Pyrophosphate (TPP)

The active coenzyme form of vitamin $\text{B}_1$ required by E1 of the PDH complex and by the $\alpha$-ketoglutarate dehydrogenase complex.

Lipoic Acid

A cofactor containing sulfhydryl groups required by enzyme E2 of the PDH complex and $I\alpha$-ketoglutarate dehydrogenase; it is specifically bound and inactivated by arsenite.

Pyruvate Dehydrogenase Kinase

A regulatory enzyme within the PDH complex that phosphorylates E1 using $\text{ATP}$, rendering the PDH complex inactive.

Pyruvate Dehydrogenase Phosphatase

A regulatory enzyme within the PDH complex that dephosphorylates E1, activating the PDH complex.

Arsenite ($\text{As}^{+3}$)

The most toxic form of arsenic that binds sulfhydryl groups of lipoic acid, inhibiting pyruvate dehydrogenase and $\alpha$-ketoglutarate dehydrogenase and leading to pyruvate/lactate accumulation.

2,3-Mercaptopropanol

A chelating agent used as a treatment for arsenic poisoning that competes with lipoic acid for binding to arsenite.

Beriberi

A nutritional deficiency disease resulting from severe vitamin $\text{B}_1$ (thiamine) deficiency, classified as wet (with edema) or dry (without edema), leading to cardiovascular and neuromuscular manifestations.

Wernicke Encephalopathy

An acute, reversible neurological disorder caused by severe thiamine deficiency, characterized by confusion, ophthalmoplegia, and gait ataxia.

Korsakoff Syndrome

A chronic, irreversible neurological disorder progressing from untreated thiamine deficiency, presenting with anterograde/retrograde amnesia, confabulation, personality changes, and mammillary body atrophy.

Pyruvate Dehydrogenase Deficiency

An X-linked recessive genetic condition caused by defects in the E1 component (PDHA1 gene) of the PDH complex, leading to impaired conversion of pyruvate to acetyl-CoA and congenital lactic acidosis.

Ketogenic Diet

A dietary regimen high in fats and low in carbohydrates used as long-term treatment for PDH deficiency to supply acetyl-CoA directly without requiring PDH activity.

Ethanol Metabolism

The hepatic metabolic breakdown of alcohol into acetate via an acetaldehyde intermediate, producing $\text{NADH}$ at both oxidation steps.

Tricarboxylic Acid (TCA) Cycle

An essential metabolic cycle located in the mitochondrial matrix that oxidizes acetyl-CoA to $\text{CO}_2$, yielding $\text{NADH}$, $\text{FADH}_2$, and $\text{GTP}$.

Amphibolic Pathway

A metabolic pathway, such as the TCA cycle, that functions in both catabolism (nutrient breakdown for energy) and anabolism (supplying biosynthetic precursors).

Anaplerotic Reactions

Chemical reactions that replenish TCA cycle intermediates that have been removed for anabolic biosynthetic pathways.

Pyruvate Carboxylase

A biotin-dependent anaplerotic enzyme that converts pyruvate, $\text{HCO}_3^-$, and $\text{ATP}$ into oxaloacetate.

Citrate Synthase

The TCA cycle enzyme that catalyzes the initial condensation of acetyl-CoA and oxaloacetate to form citrate.

Aconitase

The TCA cycle enzyme responsible for the reversible isomerization of citrate to isocitrate.

Fluoroacetate

A poison (commonly used as rat poison) that inhibits aconitase, blocking the TCA cycle.

Isocitrate Dehydrogenase

The rate-limiting enzyme of the TCA cycle that oxidizes and decarboxylates isocitrate to $\alpha$-ketoglutarate, producing the first $\text{NADH}$ and $\text{CO}_2$.

a-Ketoglutarate Dehydrogenase Complex

A multienzyme complex requiring TPP, lipoic acid, FAD, $\text{NAD}^+$, and CoA that converts $\alpha$-ketoglutarate to succinyl-CoA, producing the second $\text{NADH}$ and $\text{CO}_2$.

Succinyl-CoA Synthetase

The TCA cycle enzyme (also called succinate thiokinase) that cleaves succinyl-CoA to succinate, coupled to the substrate-level phosphorylation of $\text{GDP}$ to $\text{GTP}$.

Succinate Dehydrogenase

An inner mitochondrial membrane-bound TCA cycle enzyme (Complex II of the electron transport chain) that oxidizes succinate to fumarate while reducing FAD to $\text{FADH}_2$.

Fumarase

The TCA cycle enzyme that catalyzes the hydration of fumarate to L-malate.

Malate Dehydrogenase

The TCA cycle enzyme that oxidizes malate to regenerate oxaloacetate, producing the third molecule of $\text{NADH}$.

VOMIT Mnemonic

A mnemonic for Valine, Odd-chain fatty acids, Methionine, Isoleucine, and Threonine, which metabolize into propionyl-CoA and subsequently enter the TCA cycle as succinyl-CoA.

Net Inputs of TCA Cycle

The reactants consumed per acetyl-CoA in the TCA cycle: 3 $\text{NAD}^+$, 1 FAD, 1 $\text{GDP}$, 1 $\text{P}_i$, and 2 $\text{H}_2\text{O}$.

Net Outputs of TCA Cycle

The products yielded per acetyl-CoA oxidized in the TCA cycle: 2 $\text{CO}_2$, 3 $\text{NADH}$, 1 $\text{FADH}_2$, 1 $\text{GTP}$, and 1 $\text{CoA-SH}$.

Aerobic Net Energy Yield of Glucose

The total net energy generated from the complete oxidation of one glucose molecule under aerobic conditions, equaling $30\text{ to }32\,\text{ATP}$.

Allosteric Activators of Isocitrate Dehydrogenase

Signals indicating low cellular energy charge or muscle contraction, specifically $\text{ADP}$ and $\text{Ca}^{2+}$, which increase the rate of the TCA cycle.

Allosteric Inhibitors of Isocitrate Dehydrogenase

High-energy cellular signals, specifically $\text{ATP}$ and $\text{NADH}$, that inhibit the rate-limiting step of the TCA cycle.

Ketogenesis Trigger in TCA Inhibition

The metabolic shift in which accumulation of acetyl-CoA (due to depletion of oxaloacetate or elevated $\text{NADH}/\text{NAD}^+$ ratio) leads to ketone body production.

High-Output Cardiac Failure

A severe cardiovascular complication of wet beriberi caused by peripheral vasodilation and increased venous return to the heart.

Transketolase Activity Assay

A diagnostic blood test performed on red blood cells to assess thiamine deficiency by measuring transketolase activity before and after adding thiamine pyrophosphate.

Mammillary Bodies Atrophy

Pathological degeneration of limbic system structures seen in Korsakoff syndrome resulting from chronic thiamine deficiency, causing permanent memory loss and apathy.

Arsenic Poisoning Garlic Breath

A characteristic clinical sign seen in patients presenting with acute arsenic toxicity.

Arsenate ($\text{As}^{+5}$)

The pentavalent form of arsenic that acts toxicologically by uncoupling oxidative phosphorylation.

Substrate-Level Phosphorylation in TCA Cycle

The direct synthesis of $\text{GTP}$ from $\text{GDP}$ and inorganic phosphate driven by the cleavage of the high-energy thioester bond of succinyl-CoA.

Anaerobic Fate of Pyruvate

The reduction of pyruvate to lactate by lactate dehydrogenase, using $\text{NADH} + \text{H}^+$ to regenerate $\text{NAD}^+$ without generating additional $\text{ATP}$.

PDHA1 Gene Mutation

A mutation in the X-linked gene encoding the alpha subunit of E1 in the PDH complex, causing pyruvate dehydrogenase deficiency.

Citrate Allosteric Regulation

The regulatory functions of citrate when transported to the cytosol, where it inhibits PFK-1 in glycolysis and activates acetyl-CoA carboxylase in fatty acid synthesis.

Calcium Activation of PDH Phosphatase

The activation mechanism where $\text{Ca}^{2+}$ release during skeletal muscle contraction stimulates PDH phosphatase, converting PDH to its active form to meet energy demand.

Energetics Conservation of TCA Cycle

The high thermodynamic efficiency of the TCA cycle, conserving $207\,\text{kcal/mol}$ out of the $228\,\text{kcal/mol}$ energy available in acetyl-CoA (90% energy conservation).

Delta G Zero Prime ($\Delta G^{\circ\prime}$) of TCA Cycle

The sum of standard free energy changes of all individual TCA cycle reactions, equal to $-13\,\text{kcal/mol}$, which drives the cycle forward with energy released as heat.