Glycogen Metabolism, Citric Acid Cycle, and Oxidative Phosphorylation

Comprehensive vocabulary flashcards covering glycogen metabolism, glycogen storage diseases, the pyruvate dehydrogenase complex, the citric acid cycle, electron transport chain complexes, ATP synthase, and mitochondrial shuttle mechanisms.

Glycogen

A polymeric storage form of glucose located primarily in muscle, where its breakdown delivers glucose for contraction, and in the liver, where it serves as a reservoir for maintaining blood glucose homeostasis.

$\beta$-Granules

Cytosolic, electron-dense particles varying in size, structure, and subcellular location that cluster in the liver to form $\alpha$-granules.

$\alpha$-Granules

Protein-rich liver granules composed of $20$ to $40$ clustered $\beta$-granules that release glucose more slowly than individual $\beta$-granules, associate with smooth endoplasmic reticulum (SER) tubules, and disappear after a $24$-hour fast.

Glycogen Particle Structure

A spherical particle nucleated by a central glycogenin dimer acting as a primer, from which chains of $12$ to $14$ glucose residues extend in $12$ tiers; inner chains have two $(\alpha1 \rightarrow 6)$ branches each, while outer tier chains are unbranched.

Glycogen Phosphorylase

An enzyme that catalyzes phosphorolytic cleavage at nonreducing ends of glycogen using inorganic phosphate ($P_i$) and pyridoxal phosphate as a cofactor, releasing glucose 1-phosphate ($\text{G1P}$) until reaching four residues away from an $(\alpha1 \rightarrow 6)$ branch point.

Debranching Enzyme (Transferase Activity)

The catalytic activity of glycogen debranching enzyme that shifts a block of three glucose residues from a branch point to a nearby nonreducing end, leaving a single glucose residue attached via an $(\alpha1 \rightarrow 6)$ bond.

Debranching Enzyme ($(\alpha1 \rightarrow 6)$ Glucosidase Activity)

The hydrolytic activity of glycogen debranching enzyme that cleaves the single remaining $(\alpha1 \rightarrow 6)$-linked glucose residue at a branch point, releasing it as a free glucose molecule rather than $\text{G1P}$.

Phosphoglucomutase

An enzyme that catalyzes the reversible isomerization of glucose 1-phosphate ($\text{G1P}$) and glucose 6-phosphate ($\text{G6P}$) through a phosphorylated serine residue intermediate that creates a glucose 1,6-bisphosphate intermediate.

Glucose 6-Phosphatase System

An ER lumen-sequestered enzyme complex present only in liver and kidney cells that dephosphorylates $\text{G6P}$ transported by $T_1$ into free glucose, which exits through $T_2$ and $\text{GLUT2}$ into the blood to support systemic blood glucose homeostasis.

UDP-Glucose Pyrophosphorylase

An enzyme that catalyzes the condensation of glucose 1-phosphate ($\text{G1P}$) and uridine triphosphate ($\text{UTP}$) to produce UDP-glucose and inorganic pyrophosphate ($\text{PP}_i$), a reaction driven forward by pyrophosphate hydrolysis.

Glycogenin

A self-glucosylating protein dimer that primes glycogen synthesis by attaching a glucose residue from UDP-glucose to its $\text{Tyr}^{194}$ residue and adding seven more glucose units to build an eight-residue chain.

Glycogen Synthase

The primary chain-elongation enzyme in glycogenesis that transfers glucosyl residues from UDP-glucose to the nonreducing end of an existing glycogen chain of at least eight residues, forming $(\alpha1 \rightarrow 4)$ glycosidic linkages.

Glycogen-Branching Enzyme

An enzyme that creates $(\alpha1 \rightarrow 6)$ branches during glycogen synthesis by transferring a segment of seven residues from the nonreducing end to an interior position at least four residues away from the glycogenin core and eleven residues away from an existing branch point.

Allosteric Regulation of Glycogen Phosphorylase

Regulation of glycogen breakdown wherein glycogen phosphorylase is activated by high levels of $\text{AMP}$ and inhibited by high levels of $\text{ATP}$ and glucose 6-phosphate ($\text{G6P}$).

Allosteric Regulation of Glycogen Synthase

Regulation of glycogen synthesis wherein glycogen synthase is allosterically activated by high levels of glucose 6-phosphate ($\text{G6P}$) and inhibited by high concentrations of $\text{AMP}$, which signals cellular energy depletion.

Von Gierke Disease (Type Ia)

A glycogen storage disease caused by a genetic deficiency in glucose 6-phosphatase in the liver, leading to liver enlargement (hepatomegaly) and kidney failure.

Pompe Disease (Type II)

A glycogen storage disease caused by a deficiency in lysosomal glucosidase affecting skeletal and cardiac muscle, resulting in infantile early death, juvenile myopathy, or adult muscular dystrophy-like symptoms.

Cori Disease / Forbes Disease (Type IIIa)

A glycogen storage disease caused by a deficiency of the debranching enzyme in the liver, skeletal muscle, and cardiac muscle, characterized by an enlarged liver in infants and myopathy.

Andersen Disease (Type IV)

A glycogen storage disease caused by a genetic defect in branching enzyme affecting the liver and skeletal muscle, marked by an enlarged liver and spleen and myoglobin in the urine.

McArdle Disease (Type V)

A glycogen storage disease caused by a deficiency in muscle glycogen phosphorylase, leading to exercise-induced painful muscle cramps and myoglobinuria.

Hers Disease (Type VI)

A glycogen storage disease caused by a genetic deficiency in liver glycogen phosphorylase, primarily presenting with an enlarged liver.

Tarui Disease (Type VII)

A glycogen storage disease resulting from a defect in muscle phosphofructokinase-1 ($\text{PFK-1}$) in muscle and erythrocytes, causing muscle cramps, exercise pain, and hemolytic anemia.

Mitochondrial Pyruvate Carrier (MPC)

An $\text{H}^+$-coupled pyruvate-specific symporter located in the inner mitochondrial membrane that transports pyruvate from the cytosol into the mitochondrial matrix.

Pyruvate Dehydrogenase Complex (PDH Complex)

A multi-enzyme mitochondrial matrix complex consisting of three enzymes ($E_1$, $E_2$, $E_3$) and five cofactors that catalyzes the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA, $\text{CO}_2$, and $\text{NADH}$.

Thiamine Pyrophosphate (TPP)

A coenzyme derived from vitamin $B_1$ utilized by pyruvate dehydrogenase ($E_1$) whose thiazolium ring stabilizes carbanions to cleave bonds adjacent to a carbonyl group and transfer aldehydes.

Lipoate (Lipoic Acid)

An enzyme-bound cofactor covalently attached to a lysine residue of $E_2$ containing two thiol groups that undergo reversible oxidation to a disulfide bond, transferring both electrons and acyl groups.

Coenzyme A (CoA-SH)

A cofactor derived from vitamin $B_5$ (pantothenic acid) containing a reactive thiol ($-\text{SH}$) group that acts as an acyl group carrier by forming high-energy thioester bonds such as that in acetyl-CoA ($\Delta G^{\circ\prime} = -31.4\,\text{kJ/mol}$).

Dihydrolipoyl Transacetylase ($E_2$)

The central structural subunit of the PDH complex that uses a long lipoyllysine arm to swing substrates between active sites and transfer the acetyl group to $\text{CoA-SH}$.

Dihydrolipoyl Dehydrogenase ($E_3$)

The third subunit of the PDH complex that reoxidizes the reduced dithiol form of lipoyllysine on $E_2$ using an enzyme-bound $\text{FAD}$, followed by transferring hydride ions to $\text{NAD}^+$ to generate $\text{NADH}$.

Substrate Channeling

The movement of chemical intermediates directly between adjacent active sites of a multi-enzyme complex without diffusion into the bulk solvent, minimizing side reactions and accelerating overall catalytic flux.

Citrate Synthase

An enzyme that catalyzes the irreversible aldol condensation of oxaloacetate and acetyl-CoA to form citrate, powered by the exergonic hydrolysis of the acetyl-CoA thioester bond.

Aconitase

An iron-sulfur containing enzyme that catalyzes the reversible two-step isomerization of citrate to isocitrate by first dehydrating citrate to cis-aconitate and then rehydrating it to position the hydroxyl group on $C3$.

Isocitrate Dehydrogenase

A mitochondrial matrix enzyme that catalyzes the irreversible oxidative decarboxylation of isocitrate to $\alpha$-ketoglutarate, producing the cycle's first molecule of $\text{NADH}$ and releasing $\text{CO}_2$.

$\alpha$-Ketoglutarate Dehydrogenase Complex

A multi-enzyme complex structurally and mechanistically homologous to the PDH complex that irreversibly decarboxylates $\alpha$-ketoglutarate to succinyl-CoA, releasing the second $\text{CO}_2$ and forming a second $\text{NADH}$.

Succinyl-CoA Synthetase

An enzyme that catalyzes the reversible cleavage of the high-energy thioester bond in succinyl-CoA to form succinate, coupled to the substrate-level phosphorylation of $\text{GDP}$ or $\text{ADP}$ to $\text{GTP}$ or $\text{ATP}$.

Succinate Dehydrogenase

An enzyme of the citric acid cycle covalently linked to $\text{FAD}$ that also functions as Complex II of the electron transport chain, catalyzing the reversible oxidation of succinate to fumarate.

Fumarase

An enzyme that stereospecifically catalyzes the reversible hydration of fumarate across its double bond to generate $\text{L}$-malate via a carbanion transition state.

$\text{L}$-Malate Dehydrogenase

A mitochondrial enzyme that catalyzes the reversible oxidation of $\text{L}$-malate to oxaloacetate, producing the third and final molecule of $\text{NADH}$ in the citric acid cycle.

Amphibolic Pathway

A metabolic pathway that functions in both catabolism (oxidizing nutrients to generate energy) and anabolism (supplying precursor intermediates for biosynthesis).

Anaplerotic Reactions

Chemical reactions that replenish depleted catalytic intermediates of the citric acid cycle to ensure its continued functioning in oxidative and biosynthetic pathways.

Pyruvate Carboxylase

A biotin-dependent mitochondrial anaplerotic enzyme activated by acetyl-CoA that carboxylates pyruvate using $\text{ATP}$ and $\text{HCO}_3^-$ to form oxaloacetate.

Complex I (NADH:Ubiquinone Oxidoreductase)

A large multi-subunit complex in the inner mitochondrial membrane that transfers two electrons from $\text{NADH}$ to ubiquinone ($Q$) while pumping four protons ($4\,\text{H}^+$) from the matrix into the intermembrane space.

Complex II (Succinate Dehydrogenase)

An inner mitochondrial membrane complex that transfers electrons from succinate through $\text{FADH}_2$ and iron-sulfur centers to ubiquinone without pumping any protons across the membrane.

Complex III (Ubiquinone:Cytochrome c Oxidoreductase)

An inner mitochondrial membrane respiratory complex that transfers electrons from reduced ubiquinol ($\text{QH}_2$) to cytochrome c while pumping four protons ($4\,\text{H}^+$) into the intermembrane space.

Complex IV (Cytochrome Oxidase)

The terminal respiratory complex that accepts four electrons from reduced cytochrome c molecules to reduce molecular oxygen ($\text{O}_2$) to water ($2\,\text{H}_2\text{O}$), pumping two protons ($2\,\text{H}^+$) into the intermembrane space per electron pair.

Ubiquinone (Coenzyme Q)

A lipid-soluble, membrane-diffusible electron carrier in the inner mitochondrial membrane that carries one or two electrons and protons, coupling electron transfer between Complexes I, II, and III.

Cytochrome c

A water-soluble heme protein located in the mitochondrial intermembrane space that shuttles single electrons from Complex III to Complex IV.

Proton-Motive Force

The electrochemical potential across the inner mitochondrial membrane composed of a chemical pH gradient ($\Delta\text{pH}$, alkaline inside) and an electrical potential ($\Delta\psi$, negative inside) that powers ATP synthesis.

ATP Synthase ($F_o F_1$ Complex)

A multi-subunit enzyme complex consisting of a membrane-embedded proton pore ($F_o$) and a catalytic matrix peripheral unit ($F_1$, composition $\alpha_3\beta_3\gamma\delta\epsilon$) that synthesizes ATP as protons pass down their concentration gradient.

Binding-Change Mechanism

The catalytic cycle of ATP synthase wherein each of the three $\beta$ subunits cycles through three distinct conformations: $\beta\text{-Empty}$ (very loose binding, ATP releases), $\beta\text{-ADP}$ (loose binding of substrates), and $\beta\text{-ATP}$ (tight catalytic synthesis of ATP).

Adenine Nucleotide Translocase

An inner mitochondrial membrane antiporter that exports $\text{ATP}^{4-}$ from the matrix into the intermembrane space in exchange for import of $\text{ADP}^{3-}$, driven by the membrane's electrical potential.

Phosphate Translocase

An inner mitochondrial membrane symporter that brings inorganic phosphate ($\text{H}_2\text{PO}_4^-$) into the matrix along with one proton ($\text{H}^+$), utilizing the chemical proton gradient.

Antimycin A

A toxic respiratory inhibitor that blocks electron transfer from cytochrome b to cytochrome $c_1$ in Complex III, thereby halting oxygen reduction and coupled ATP synthesis.

Glycerol 3-Phosphate Shuttle

An electron shuttle active in skeletal muscle and the brain that transfers reducing equivalents from cytosolic $\text{NADH}$ to mitochondrial $\text{FAD}$, entering the respiratory chain at ubiquinone/Complex III and yielding $1.5\,\text{ATP}$ per $\text{NADH}$.

Malate-Aspartate Shuttle

An electron shuttle active in liver, kidney, and heart tissue that transfers cytosolic reducing equivalents from $\text{NADH}$ to regenerate mitochondrial matrix $\text{NADH}$, entering at Complex I and yielding $2.5\,\text{ATP}$ per $\text{NADH}$.

P/O Ratio (Phosphate/Oxygen Ratio)

The stoichiometric ratio of moles of inorganic phosphate ($P_i$) consumed to synthesize ATP per mole of oxygen atoms reduced; equal to $2.5$ for $\text{NADH}$ ($10\,\text{protons}/4\,\text{protons}$) and $1.5$ for $\text{FADH}_2$ ($6\,\text{protons}/4\,\text{protons}$).

Substrate-Level Phosphorylation

The direct enzymatic formation of $\text{ATP}$ or $\text{GTP}$ by the transfer of a phosphate group from a phosphorylated metabolic intermediate, occurring independently of oxygen in glycolysis and the citric acid cycle.

Oxidative Phosphorylation

The synthesis of $\text{ATP}$ from $\text{ADP}$ and $P_i$ driven by the flow of protons back across the inner mitochondrial membrane via ATP synthase, utilizing the electrochemical energy generated by electron transport to molecular oxygen.