Kreb's Cycle and Electron Transport Chain

Flashcards covering the Krebs Cycle, Electron Transport Chain, oxidative phosphorylation, associated enzymes, regulatory mechanisms, inhibitors, and biomedical importance based on the lecture notes.

Krebs Cycle

Also known as tricarboxylic acid cycle (TCA cycle) and citric acid cycle; involved in oxidative catabolism converting carbohydrates, amino acids, and fatty acids to carbon dioxide; provides energy for ATP production and occurs in mitochondria.

Tricarboxylic Acid Cycle (TCA cycle)

Another name for the Krebs Cycle, which is involved in oxidative catabolism.

Citric Acid Cycle

Another name for the Krebs Cycle, which is involved in oxidative catabolism.

Aerobic Pathway

A metabolic pathway, like the Krebs cycle, that requires oxygen.

Anabolic reactions

Reactions where the TCA cycle provides intermediates for synthesis, such as glucose formation, amino acid synthesis, and heme synthesis.

Acetyl Coenzyme A (acetyl-CoA)

The substrate for the Krebs cycle, produced from the oxidation of fatty acids, glucose, amino acids, acetate, and ketone bodies.

Pyruvate dehydrogenase complex (PDHC)

A multienzyme complex that converts pyruvate to acetyl-CoA, allowing it to enter the Krebs cycle.

Pyruvate decarboxylase (E1)

A component of the PDHC that requires thiamine pyrophosphate (TPP).

Dihydrolipoyl transacetylase (E2)

A component of the PDHC that requires Lipoate and CoA.

Dihydrolipoyl dehydrogenase (E3)

A component of the PDHC that requires FAD and NAD+.

Thiamine pyrophosphate (TPP)

A coenzyme required by E1 of the PDHC, derived from thiamine (Vitamin B1).

Flavin adenine dinucleotide (FAD)

A coenzyme required by E3 of the PDHC, derived from riboflavin (Vitamin B2).

Nicotinamide adenine dinucleotide (NAD)

A coenzyme required by E3 of the PDHC, derived from niacin (Vitamin B3).

Coenzyme A (CoA)

A coenzyme required by E2 of the PDHC, derived from pantothenic acid (Vitamin B5).

Lipoic acid

A coenzyme required by E2 of the PDHC, which is not derived from a vitamin.

Wernicke-Korsakoff syndrome

An encephalopathy-psychosis syndrome caused by thiamine deficiency, often seen in individuals with alcohol use disorder.

PDH kinase

An enzyme that phosphorylates and inactivates E1 of the PDHC, allosterically activated by ATP, acetyl CoA, and NADH.

PDH phosphatase

An enzyme that dephosphorylates and activates E1 of the PDHC.

Congenital lactic acidosis

A condition that can result from a deficiency of E1 of the PDHC, leading to neurodegeneration and muscle spasticity.

Dehydrogenases

Enzymes involved in four of the eight steps of the Krebs cycle, responsible for oxidation-reduction reactions.

Isomerases

Enzymes involved in two of the eight steps of the Krebs cycle, responsible for interconverting isomers.

Citrate synthase

The enzyme that catalyzes the aldol condensation of acetyl group and oxaloacetate to form citrate.

Isocitrate dehydrogenase

Enzyme that catalyzes the irreversible oxidative decarboxylation of isocitrate to α-ketoglutarate, producing the first NADH and CO2, and representing a rate-limiting step of the TCA cycle.

Rate-limiting step of TCA cycle

The reaction catalyzed by isocitrate dehydrogenase, which is the formation of α-ketoglutarate from isocitrate.

α-ketoglutarate dehydrogenase complex

The enzyme complex that catalyzes the oxidative decarboxylation of α-ketoglutarate to succinyl CoA, producing the second NADH and CO2.

Succinate thiokinase (succinyl CoA synthetase)

The enzyme that cleaves the high-energy thioester bond of succinyl CoA, resulting in the phosphorylation of GDP to GTP (substrate level phosphorylation).

Substrate level phosphorylation

The direct transfer of a phosphate group from a substrate to ADP or GDP to form ATP or GTP, as seen in the succinyl CoA to succinate step of the Krebs cycle.

Succinate dehydrogenase

The only enzyme of the Krebs cycle located in the inner mitochondrial membrane, which oxidizes succinate to fumarate and functions as Complex II of the Electron Transport Chain.

Complex II of the ETC

Also known as succinate-Q reductase, it consists of succinate dehydrogenase, glycerol-3-phosphate dehydrogenase, and fatty acyl-CoA dehydrogenase.

Fumarase

The enzyme that catalyzes the hydration of fumarate to malate.

Malate dehydrogenase

The enzyme that catalyzes the oxidation of malate to oxaloacetate, forming NADH.

ATP production in Krebs Cycle

Oxidation of one NADH by the ETC leads to 3 ATP, whereas oxidation of FADH2 produces 2 ATP.

Irreversible reactions in Krebs cycle

Reactions catalyzed by citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase, characterized by largely negative free energy values.

Reversible reactions in Krebs cycle

Reactions catalyzed by aconitase and malate dehydrogenase, characterized by positive free energy values.

Key regulatory enzymes of Krebs Cycle

Citrate synthase, isocitrate dehydrogenase, and the α-ketoglutarate dehydrogenase complex.

High-energy state (TCA cycle regulation)

Characterized by high ATP and NADH levels, leading to a decrease in TCA cycle activity.

Low-energy state (TCA cycle regulation)

Characterized by high ADP or Pi levels, leading to an increase in TCA cycle activity.

Amphibolic pathway

A metabolic pathway, like the Krebs cycle, that serves both catabolic (breakdown) and anabolic (synthesis) processes.

Anaplerotic reactions

Reactions that replenish intermediates in the TCA cycle.

Pyruvate dehydrogenase complex (PDHC) impairment

Caused by mutations or thiamine deficiency, leading to increased pyruvate levels, lactic acidosis, neurodegeneration, muscle spasticity, and potentially death.

Ketogenic diet

A high-fat and low-carbohydrate diet used as a treatment for PDHC impairment.

Electron Transport Chain (ETC)

A series of electron carriers that oxidize NADH and FADH2, ultimately reducing oxygen to water and generating ATP.

Inner mitochondrial membrane

The location of the electron transport chain, impermeable to small ions, H+, and small molecules without carrier proteins.

Outer mitochondrial membrane

Contains porin channels, making it freely permeable to ions and small molecules.

Complex I (NADH dehydrogenase)

Accepts electrons from NADH, oxidizing it back to NAD+, and contains tightly bound flavin mononucleotide (FMN).

Maleate Aspartate Shuttle

A shuttle system that indirectly delivers reducing equivalents from cytosolic NADH into the mitochondrial matrix to Complex I, producing 2.5 ATPs.

Glycerol Phosphate Shuttle

A shuttle system that indirectly delivers reducing equivalents from cytosolic NADH to FAD (Complex II), producing 1.5 ATPs.

Flavin mononucleotide (FMN)

A molecule tightly bound to Complex I (NADH dehydrogenase) that accepts two electrons and H+ from NADH to become FMNH2.

Coenzyme Q (Ubiquinone)

A lipophilic electron carrier in the ETC, which accepts electrons from Complex I and Complex II, has a long hydrophobic isoprenoid tail, and acts as an antioxidant.

Complex III (Cytochrome b/c1 cytochrome c reductase)

Contains heme groups and accepts electrons from Coenzyme Q, transferring them to Cytochrome c.

Cytochrome c

An electron carrier in the ETC containing a heme group and Cu, which accepts electrons from Complex III and transfers them to Complex IV.

Complex IV (Cytochrome c oxidase)

The enzyme complex that accepts electrons from Cytochrome c, transferring them to O2 (the final electron acceptor) to form H2O.

Complex V (ATP synthase)

Contains a proton channel that allows protons to move back into the mitochondrial matrix from the intermembrane space, utilizing the proton gradient energy to synthesize ATP.

Oxidative phosphorylation

The process where ATP is synthesized from ADP using the energy derived from the electron transport chain, explained by the chemiosmotic theory.

Chemiosmotic theory

Hypothesis explaining how free energy from electron transport is used to produce ATP, involving the pumping of H+ across the inner mitochondrial membrane to create a proton motive force.

Proton motive force

The combined pH difference and membrane potential difference created by H+ pumping across the inner mitochondrial membrane, used by ATP synthase to synthesize ATP.

Site-specific inhibitors of ETC

Substances that bind to specific components of the electron transport chain, blocking oxidation-reduction reactions, inhibiting electron passage, and preventing ATP synthesis.

Rotenone

An insecticide that inhibits Complex I (NADH dehydrogenase) of the ETC.

Amytal

A barbiturate that inhibits Complex I (NADH dehydrogenase) of the ETC.

Antimycin

An antibiotic that inhibits Complex III (Cytochrome reductase) of the ETC.

Cyanide

A poison that binds to Fe3+ in Complex IV (Cytochrome c oxidase), inhibiting electron transfer to O2 and ATP synthesis, causing hypoxic symptoms.

Carbon monoxide (CO)

A combustion gas that binds to Complex IV (Cytochrome c oxidase), less tightly than cyanide and hemoglobin, causing symptoms like headache, nausea, tachycardia, depression, and potentially coma/fatal outcomes.

Azide

A propellant that inhibits Complex IV (Cytochrome c oxidase).

Hydrogen sulfide (H2S)

A sewage gas that inhibits Complex IV (Cytochrome c oxidase).

Hyperammonemia

A condition caused by hepatitis or liver cirrhosis, which depletes Krebs cycle intermediates, inhibits α-ketoglutarate oxidative decarboxylation, reduces ATP formation, and can lead to loss of consciousness, convulsions, and coma.

Leigh disease

A genetic disease caused by pyruvate carboxylase deficiency, leading to lactic acidosis, loss of cerebral neurons, and impaired synthesis of glutamine important for neuronal survival.

Krebs cycle intermediates (anabolic precursors)

Precursors supplied by the Krebs cycle for anabolic pathways, including oxaloacetate and malate for glucose, succinyl-CoA for porphyrins, 2-oxoglutarate and oxaloacetate for amino acids, and citrate for fatty acids and isoprenoids.

Pyruvate carboxylase deficiency

The cause of Leigh disease, where pyruvate cannot be converted to oxaloacetate for the TCA cycle, leading to increased lactate formation and lactic acidosis.

Number of NADH molecules produced per turn of the Krebs cycle

3 NADH molecules are produced: one from isocitrate, one from \alpha-ketoglutarate, and one from malate.

Number of FADH_2 molecules produced per turn of the Krebs cycle

1 FADH_2 molecule is produced from succinate by succinate dehydrogenase.

Number of GTP molecules produced per turn of the Krebs cycle

1 GTP molecule is produced from succinyl CoA by succinate thiokinase (substrate level phosphorylation).

Total ATP equivalents generated per acetyl-CoA through Krebs cycle and ETC

Utilizing the values of 3 ATP per NADH and 2 ATP per FADH2 from the Electron Transport Chain, plus 1 GTP (equivalent to 1 ATP), a total of 12 ATP equivalents (3 \times 3 ATP from NADH + 1 \times 2 ATP from FADH2 + 1 ATP from GTP) are generated per acetyl-CoA.

How is Citrate Synthase regulated?

It is inhibited by ATP, NADH, succinyl-CoA, and citrate. It is activated by ADP.

How is Isocitrate Dehydrogenase regulated?

It is inhibited by ATP and NADH. It is activated by ADP and Ca^{2+}.

How is the \alpha-Ketoglutarate Dehydrogenase Complex regulated?

It is inhibited by succinyl-CoA, NADH, and ATP. It is activated by Ca^{2+}.

Catabolic role of the Krebs cycle

It is involved in the oxidative breakdown of carbohydrates, fatty acids, and amino acids to produce energy (ATP) through the generation of reducing equivalents (NADH and FADH_2).

Final electron acceptor of the Electron Transport Chain

Oxygen (O2), which is reduced to water (H2O).

Mechanism of proton gradient formation in the ETC

Electrons flowing through Complexes I, III, and IV drive the pumping of protons (H^+) from the mitochondrial matrix into the intermembrane space, creating an electrochemical gradient.

Overall impact of site-specific inhibitors on the ETC

They block electron flow at specific points, preventing oxygen consumption, halting proton pumping, and thereby inhibiting the synthesis of ATP by oxidative phosphorylation.

Central biochemical importance of the Krebs cycle

It serves as the final common pathway for the oxidation of all major fuel molecules and provides crucial intermediates for various anabolic (biosynthetic) pathways.

Mechanism by which hyperammonemia leads to loss of consciousness

Elevated ammonia levels react with \alpha-ketoglutarate to form glutamate, which is then converted to glutamine. This depletes the Krebs cycle intermediate \alpha-ketoglutarate, impairing the cycle's function, reducing ATP production, and leading to neuronal dysfunction and coma.

Where in the cell does the Krebs cycle take place?

Mitochondrial matrix

Which coenzyme is NOT derived from vitamins in the Krebs cycle?

Lipoic acid

How many molecules of NADH are produced per turn of the citric acid cycle?

3

Which enzyme in the citric acid cycle catalyzes a reaction that results in the production of CO_2 and NADH?

\alpha-ketoglutarate dehydrogenase complex

Which intermediate of the citric acid cycle is used in the synthesis of heme, an important component of hemoglobin?

Succinyl-CoA

FAD, which is required for the oxidation of succinate to fumarate, is derived from which vitamin?

Vitamin B2 (Riboflavin)

Which intermediate of the citric acid cycle is directly involved in the initiation of fatty acid synthesis?

Citrate

Which of the following is a known inhibitor of Complex I in the electron transport chain?

Rotenone

Which coenzyme transfers electrons from Complex I and Complex II to Complex III in the electron transport chain?

Coenzyme Q

Which of the following inhibits Complex IV (Cytochrome c oxidase) by preventing the transfer of electrons to oxygen?

Cyanide