TCA Cycle and Electron Transport System – Vocabulary Flashcards

A comprehensive set of vocabulary flashcards covering the TCA cycle, PDH complex, anaplerosis, and the electron transport chain with key enzymes, cofactors, shuttles, regulation, and inhibitors.

TCA cycle (Krebs cycle, Citric acid cycle)

A central metabolic pathway located in the mitochondrial matrix that completely oxidizes the acetyl group from acetyl-CoA to two molecules of carbon dioxide (CO_2). It serves as the final common pathway for the oxidation of carbohydrates, fats, and proteins, producing the reduced coenzymes NADH and FADH2, along with one molecule of GTP (or ATP) per cycle. These reduced coenzymes then donate their electrons to the Electron Transport System (ETS) for the production of a large amount of ATP via oxidative phosphorylation, thus serving as the main generator of cellular energy.

Acetyl-CoA

A two-carbon acetyl donor molecule that acts as a crucial intermediate in metabolism. It is primarily formed from pyruvate (the end product of glycolysis) by the pyruvate dehydrogenase (PDH) complex, and also from the β-oxidation of fatty acids and certain amino acids. In the TCA cycle, acetyl-CoA combines with the four-carbon compound oxaloacetate to initiate the cycle by forming citrate.

Pyruvate dehydrogenase (PDH) Complex

A large, multisubunit enzyme complex located in the mitochondrial matrix that catalyzes the irreversible oxidative decarboxylation of pyruvate (a three-carbon molecule) to acetyl-CoA (a two-carbon molecule), along with the production of NADH and CO_2. This reaction is a critical regulatory step, linking glycolysis to the TCA cycle and subsequent oxidative phosphorylation. It requires five cofactors: thiamine pyrophosphate (TPP), α-lipoic acid, coenzyme A (CoA), flavin adenine dinucleotide (FAD), and nicotinamide adenine dinucleotide (NAD+), and is tightly regulated by kinase/phosphatase activity and product inhibition.

Thiamine pyrophosphate (TPP)

A coenzyme derived from vitamin B_1 (thiamine) that is essential for the activity of the Pyruvate Dehydrogenase (PDH) complex and other α-keto acid dehydrogenases. TPP functions by forming a covalent adduct with the carbonyl carbon of pyruvate (or other α-keto acids), facilitating its decarboxylation and the subsequent transfer of the aldehyde group.

α-Lipoic acid (lipoamide)

A coenzyme covalently linked to a lysine residue (forming lipoamide) that is crucial for the Pyruvate Dehydrogenase (PDH) complex and α-ketoglutarate dehydrogenase. It functions as a swing arm, transferring both acyl groups and electrons between the active sites of these multienzyme complexes during the oxidative decarboxylation process.

Coenzyme A (CoA)

A prominent coenzyme derived from vitamin B_5 (pantothenic acid) that contains a reactive thiol group (-SH). It functions as an acyl group carrier in many metabolic reactions, forming a high-energy thioester bond with acyl groups (e.g., acetyl group to form acetyl-CoA). In the PDH complex and the TCA cycle, CoA accepts the acetyl group to form acetyl-CoA, which then enters the TCA cycle.

Flavin adenine dinucleotide (FAD)

A redox coenzyme that can accept two hydrogen atoms (two electrons and two protons) to become its reduced form, FADH_2. It is a prosthetic group tightly bound to flavoproteins, such as Complex II (Succinate dehydrogenase) in the ETS and various dehydrogenases in the TCA cycle (e.g., PDH, α-ketoglutarate dehydrogenase), where it facilitates electron transfer reactions by being reversibly oxidized and reduced.

Nicotinamide adenine dinucleotide (NAD+)

An oxidized coenzyme that is a crucial electron acceptor in many catabolic pathways, including glycolysis, the PDH complex, and the TCA cycle. It accepts two electrons and one proton (H^+) to form its reduced form, NADH. The NADH then donates its electrons to the Electron Transport System (ETS) to generate ATP via oxidative phosphorylation.

Isocitrate dehydrogenase

A key regulatory and rate-limiting enzyme of the TCA cycle and a major control point. It catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, producing the first molecule of NADH and the first molecule of CO_2 released in the TCA cycle. This enzyme is allosterically activated by ADP and Ca^{2+}, which signal low energy status and muscle contraction, respectively. Conversely, it is inhibited by NADH and ATP, which signal high energy levels within the cell.

Citrate synthase

The first enzyme of the TCA cycle, responsible for the condensation of the four-carbon compound oxaloacetate with the two-carbon acetyl-CoA to form the six-carbon citrate. Its activity is inhibited by high levels of its product citrate, as well as other indicators of high energy status or ample carbon skeletons, such as succinyl-CoA, NADH, and ATP. In the liver, ADP can relieve ATP inhibition, reflecting tissue-specific regulation.

α-Ketoglutarate dehydrogenase

A large, multisubunit enzyme complex within the TCA cycle that is structurally and mechanistically similar to the Pyruvate Dehydrogenase (PDH) complex. It catalyzes the oxidative decarboxylation of α-ketoglutarate to succinyl-CoA, producing the second molecule of NADH and CO_2 in the cycle. This complex requires the same five cofactors as PDH (TPP, lipoic acid, CoA, FAD, NAD+) and is regulated by Ca^{2+} and AMP (activators) and NADH and ATP (inhibitors), reflecting the overall energy state of the cell.

Anaplerosis

Metabolic reactions that replenish the intermediates of the TCA cycle when they are drawn off for various biosynthetic pathways. For example, oxaloacetate and α-ketoglutarate can be used to synthesize amino acids, while succinyl-CoA can be used for heme synthesis. Without anaplerotic reactions, the TCA cycle would grind to a halt due to insufficient oxaloacetate to condense with acetyl-CoA, thus preventing energy production.

Pyruvate carboxylase

A mitochondrial, biotin-dependent enzyme that catalyzes a key anaplerotic reaction: the carboxylation of pyruvate to oxaloacetate, requiring ATP and HCO3^- (CO2). This reaction is crucial for replenishing oxaloacetate, thereby ensuring the continued operation of the TCA cycle. It also plays a vital role in gluconeogenesis by providing the initial substrate for glucose synthesis from non-carbohydrate precursors.

Oxidative phosphorylation

The metabolic pathway in the mitochondria (or plasma membrane of bacteria) in which the energy released by the oxidation of substrates (via the Electron Transport System (ETS)) is used to generate a proton gradient (proton motive force) across the inner mitochondrial membrane. This electrochemical gradient then drives the synthesis of ATP from ADP and inorganic phosphate (P_i) by ATP synthase (Complex V), representing the major ATP-generating process in aerobic organisms.

Electron Transport System (ETS)

A series of four large protein complexes (Complexes I-IV) and two mobile electron carriers (ubiquinone/CoQ and cytochrome c) embedded in the inner mitochondrial membrane. The primary function of the ETS is to sequentially transfer electrons, primarily from NADH and FADH2 (generated from glycolysis and the TCA cycle), ultimately to molecular oxygen (O2), which is reduced to water (H_2O). This electron flow releases energy, which is used to pump protons (H^+) from the mitochondrial matrix into the intermembrane space, thereby establishing an electrochemical gradient known as the proton motive force that drives ATP synthesis.

Complex I (NADH dehydrogenase)

The first large protein complex of the Electron Transport System (ETS), also known as NADH oxidoreductase. It accepts two electrons from NADH (oxidizing it to NAD^+), transfers them to flavin mononucleotide (FMN), then through a series of iron-sulfur (Fe-S) clusters, and finally donates them to ubiquinone (CoQ). This electron transfer is coupled to the pumping of four protons (4H^+) from the mitochondrial matrix to the intermembrane space, contributing significantly to the proton motive force.

Complex II (Succinate dehydrogenase)

The second protein complex of the Electron Transport System (ETS), uniquely also functioning as an enzyme in the TCA cycle (succinate dehydrogenase). It oxidizes succinate to fumarate, reducing its covalently bound FAD to FADH2. The electrons from FADH2 are then transferred through Fe-S clusters directly to ubiquinone (CoQ). Notably, Complex II does not pump protons across the inner mitochondrial membrane, contributing electrons to the ETS at a lower energy level than Complex I.

Coenzyme Q (CoQ, ubiquinone)

A small, lipid-soluble benzoquinone molecule that acts as a mobile electron carrier within the inner mitochondrial membrane. It accepts electrons from both Complex I and Complex II (and other mitochondrial dehydrogenases) and carries these electrons to Complex III (cytochrome bc1 complex). Its hydrophobic nature allows it to freely diffuse within the lipid bilayer, shuttling electrons between the fixed complexes.

Complex III (cytochrome bc1 complex)

A protein complex in the Electron Transport System (ETS) that accepts electrons from ubiquinone (CoQ) and transfers them to cytochrome c. It contains cytochromes bH and bL, and an iron-sulfur protein. Complex III actively pumps protons (4H^+ per reduced CoQ molecule) across the inner mitochondrial membrane via a mechanism called the Q cycle, which allows for efficient electron transfer and proton pumping by utilizing two pathways for CoQ oxidation and reduction.

Cytochrome c

A small, soluble, heme-containing protein located in the intermembrane space of the mitochondria. It acts as a mobile electron carrier, accepting a single electron from Complex III (cytochrome bc1 complex) and then diffusing along the outer surface of the inner mitochondrial membrane to donate this electron to Complex IV (cytochrome c oxidase). This makes it a crucial link between Complex III and Complex IV in the Electron Transport System (ETS).

Complex IV (cytochrome c oxidase)

The final protein complex of the Electron Transport System (ETS), also known as cytochrome c oxidase. It accepts electrons from cytochrome c and catalyzes the two-electron reduction of molecular oxygen (O2) to water (H2O), consuming four electrons and four protons per O2 molecule. This complex contains copper (Cu) centers and heme a3 groups, which facilitate the electron transfer. Complex IV also pumps two protons (2H^+) per pair of electrons across the inner mitochondrial membrane, further contributing to the proton motive force.

Complex V (ATP synthase)

A large, multi-subunit enzyme complex (also known as FoF1 ATPase) embedded in the inner mitochondrial membrane that catalyzes the synthesis of ATP from ADP and inorganic phosphate (Pi). It functions by harnessing the electrochemical potential energy stored in the proton motive force (pmf). The Fo domain acts as a proton channel embedded in the membrane, allowing protons to flow back into the matrix, which causes its rotation. This rotation is coupled to conformational changes in the F_1 catalytic domain (protruding into the matrix), driving the synthesis and release of ATP (chemiosmotic coupling).

Proton motive force (pmf)

The electrochemical potential energy stored across the inner mitochondrial membrane as a result of the Electron Transport System (ETS) pumping protons (H^+) from the mitochondrial matrix to the intermembrane space. It consists of two components: the electrical potential energy (due to charge separation, with the outside being more positive) and the chemical potential energy (due to the pH gradient, with a lower pH in the intermembrane space). This stored energy is then utilized by ATP synthase to drive the synthesis of ATP.

Chemiosmotic hypothesis

A fundamental theory proposed by Peter Mitchell, describing the mechanism by which oxidative phosphorylation occurs. It postulates that the energy released from the transfer of electrons through the Electron Transport System (ETS) is used to pump protons (H^+) across the inner mitochondrial membrane, establishing an electrochemical proton gradient (the proton motive force). This gradient then provides the energy to drive the synthesis of ATP by ATP synthase, rather than directly coupling electron transport to ATP synthesis.

Glycerol phosphate shuttle

A metabolic shuttle system that transfers electrons from cytosolic NADH (generated during glycolysis) into the mitochondria in some tissues (e.g., muscle, brain). Cytosolic glycerol-3-phosphate dehydrogenase reduces dihydroxyacetone phosphate to glycerol-3-phosphate, oxidizing NADH to NAD^+^. Glycerol-3-phosphate then transfers its electrons to an FAD-linked mitochondrial glycerol-3-phosphate dehydrogenase, which reduces FAD to FADH_2. These electrons are then passed to ubiquinone (CoQ) in the Electron Transport System (ETS), resulting in a yield of approximately 1.5 ATP per cytosolic NADH transferred, a lower yield than the malate-aspartate shuttle.

Malate-aspartate shuttle

A highly efficient metabolic shuttle system primarily active in the heart, liver, and kidney, which transfers electrons from cytosolic NADH (generated during glycolysis) into the mitochondrial matrix. It involves a series of transaminases and dehydrogenases, using malate to carry reducing equivalents into the mitochondria and aspartate to return components to the cytosol. Inside the mitochondria, NAD^+ is reduced to NADH, which then feeds its electrons into Complex I of the Electron Transport System (ETS). This shuttle results in a higher ATP yield of approximately 2.5 ATP per cytosolic NADH transferred, preserving the full energetic potential of NADH.

ATP/ADP translocase

A highly abundant integral membrane protein in the inner mitochondrial membrane walls that functions as an antiporter, facilitating the exchange of ATP from the mitochondrial matrix (where it's produced) for ADP from the intermembrane space (where it's consumed). This exchange is driven by the proton motive force, as ATP^{-4} is exchanged for ADP^{-3}, contributing to the electrochemical gradient. This translocase is essential for maintaining the cellular energy currency and allowing newly synthesized ATP to be used in the cytosol.

Citrate shuttle

A metabolic pathway that transfers citrate from the mitochondrial matrix to the cytosol. Once in the cytosol, citrate is cleaved by ATP-citrate lyase (requiring ATP) into acetyl-CoA and oxaloacetate. The cytosolic acetyl-CoA is then utilized for fatty acid synthesis and cholesterol synthesis, representing a crucial link between carbohydrate metabolism (via TCA cycle) and lipid synthesis.

Fluoroacetate (and fluorocitrate)

A highly toxic environmental poison that acts as a suicide inhibitor of the TCA cycle. Fluoroacetate is converted in the cell to fluoroacetyl-CoA, which then condenses with oxaloacetate (catalyzed by citrate synthase) to form fluorocitrate. Fluorocitrate is a potent competitive inhibitor of aconitase, preventing the isomerization of citrate to isocitrate, thereby effectively blocking the entire TCA cycle and inhibiting energy production.

Aconitase

An enzyme in the TCA cycle that catalyzes the reversible isomerization of citrate to isocitrate, with cis-aconitate as an enzyme-bound intermediate. This reaction involves the dehydration and rehydration of citrate. Aconitase is inhibited by fluorocitrate, a toxic compound derived from fluoroacetate, which thereby halts the TCA cycle.

Succinyl-CoA synthetase

The only enzyme in the TCA cycle that catalyzes substrate-level phosphorylation. It converts succinyl-CoA to succinate, driving the synthesis of a high-energy phosphate bond. In most tissues, this typically involves the phosphorylation of GDP to GTP. Some isozymes can phosphorylate ADP to ATP. The GTP produced can be readily converted to ATP by nucleoside diphosphate kinase, making this a direct yield of energy from the TCA cycle.

Oxygen in cellular respiration

Molecular oxygen (O2) serves as the final electron acceptor in the Electron Transport System (ETS), specifically at Complex IV (cytochrome c oxidase). It accepts electrons after they have passed through the entire chain and is reduced to water (H2O). This crucial role ensures the continuous flow of electrons through the ETS, thereby maintaining the proton motive force and enabling the majority of ATP production through oxidative phosphorylation in aerobic organisms. Without oxygen, electron flow stops, leading to a rapid cessation of ATP synthesis.