Cellular Respiration: Glycolysis, the Citric Acid Cycle, and Oxidative Phosphorylation

Vocabulary practice flashcards covering glycolysis, gluconeogenesis, the pyruvate dehydrogenase complex, the citric acid cycle, and oxidative phosphorylation based on lecture notes and exam review materials.

Glycolysis

A central metabolic pathway that converts one molecule of glucose into two molecules of pyruvate, yielding a net production of $2\text{ ATP}$ and $2\text{ NADH}$.

Irreversible Glycolytic Enzymes

Hexokinase, phosphofructokinase-1 (PFK-1), and pyruvate kinase; these three enzymes catalyze reactions that are irreversible under physiological conditions.

Hexokinase

The glycolytic enzyme that phosphorylates glucose to glucose 6-phosphate; this phosphorylation attaches a negative charge that prevents glucose from readily crossing the plasma membrane, trapping it inside the cell.

Phosphofructokinase-1 (PFK-1)

The key regulatory enzyme catalyzing the first committed step of glycolysis (conversion of fructose 6-phosphate to fructose 1,6-bisphosphate); it is allosterically inhibited by high concentrations of $ATP$ and citrate, and activated by $AMP$ and fructose 2,6-bisphosphate.

Phosphoglucose Isomerase

The enzyme that isomerizes glucose 6-phosphate (an aldose) into fructose 6-phosphate (a ketose), arranging the carbonyl group to permit subsequent aldol cleavage into two three-carbon fragments.

Triose Phosphate Isomerase (TPI)

The enzyme interconverting dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate; although equilibrium favors DHAP, the reaction proceeds forward toward glyceraldehyde 3-phosphate because it is continually consumed by the subsequent glycolytic reaction.

Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH)

The glycolytic enzyme that oxidizes glyceraldehyde 3-phosphate, conserving oxidation energy primarily through the formation of a high-energy acyl phosphate bond in 1,3-bisphosphoglycerate while reducing $NAD^+$ to $NADH$.

Substrate-Level Phosphorylation

The direct synthesis of $ATP$ (or $GTP$) coupled to the transfer of a phosphoryl group from a high-energy metabolic intermediate to ADP (or GDP); in glycolysis, this occurs directly at reactions 7 (phosphoglycerate kinase) and 10 (pyruvate kinase).

Pyruvate Kinase

The enzyme catalyzing the tenth reaction of glycolysis, transferring a phosphoryl group from phosphoenolpyruvate (PEP) to ADP to produce ATP and pyruvate; the reaction is driven forward strongly because the initial enol product rapidly tautomerizes to the more stable keto form.

Pyruvate Kinase Reaction

The substrate-level phosphorylation step that converts phosphoenolpyruvate (PEP) and ADP into ATP and pyruvate, catalyzed by pyruvate kinase.

Lactate Fermentation

An anaerobic pathway whose essential metabolic purpose is to regenerate $NAD^+$ from $NADH$ under oxygen-limiting conditions so that glycolysis can continue producing ATP.

Adenylate Kinase

An enzyme that interconverts adenine nucleotides ($2\text{ ADP} \rightleftharpoons \text{ATP} + \text{AMP}$), amplifying small relative decreases in cellular $ATP$ into much larger relative changes in $AMP$, making $AMP$ a sensitive indicator of low energy charge.

Fructose 2,6-Bisphosphate

A potent allosteric activator of phosphofructokinase-1 (PFK-1) that relieves ATP-mediated inhibition and stimulates glycolytic flux.

Glucokinase

A liver isozyme of hexokinase characterized by a lower affinity for glucose (higher $K_m$) and an absence of product inhibition by glucose 6-phosphate.

Hepatic Fructose Metabolism

Metabolism of dietary fructose in the liver that enters glycolysis downstream of PFK-1 as triose intermediates, bypassing the primary regulatory checkpoint of glycolysis and favoring unregulated fatty acid synthesis.

Gluconeogenic Bypass of Pyruvate Kinase

A two-step pathway catalyzed by pyruvate carboxylase (converting pyruvate to oxaloacetate) and phosphoenolpyruvate carboxykinase (converting oxaloacetate to phosphoenolpyruvate) to bypass the irreversible pyruvate kinase step.

Pyruvate Carboxylase

A mitochondrial gluconeogenic enzyme that converts pyruvate into oxaloacetate; it is allosterically activated by acetyl CoA and uses biotin as a prosthetic group to carry activated $CO_2$.

Futile Cycle

A wasteful metabolic cycle that occurs if opposing irreversible pathways (such as glycolysis and gluconeogenesis) operate simultaneously at the same rate, resulting in the net consumption of ATP and dissipation of chemical energy as heat.

Pyruvate Dehydrogenase (PDH) Complex

A mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate under aerobic conditions to yield acetyl CoA, $CO_2$, and $NADH$; organized as a complex to channel intermediates directly between active sites and minimize competing side reactions.

PDH Coenzymes

The five essential cofactors utilized by the pyruvate dehydrogenase complex: thiamine pyrophosphate (TPP), lipoic acid (lipoamide), coenzyme A (CoA), flavin adenine dinucleotide (FAD), and nicotinamide adenine dinucleotide ($NAD^+$).

Lipoamide Arm

A flexible coenzyme tether covalently attached to a lysine residue on the E2 core of the pyruvate dehydrogenase complex that swings reaction intermediates sequentially between the active sites of E1, E2, and E3.

Citrate Synthase

The enzyme initiating the citric acid cycle by condensing acetyl CoA with oxaloacetate to form citrate; it binds oxaloacetate first to create the binding site for acetyl CoA, thereby preventing unproductive, premature hydrolysis of the acetyl CoA thioester bond.

Aconitase

An iron-sulfur containing enzyme that isomerizes citrate into isocitrate via the enzyme-bound intermediate cis-aconitate, repositioning the hydroxyl group from a tertiary carbon to a secondary carbon suitable for oxidation.

Isocitrate

A six-carbon tricarboxylic acid intermediate of the citric acid cycle formed in the aconitase reaction that undergoes oxidative decarboxylation by isocitrate dehydrogenase.

Oxidative Decarboxylations of the Citric Acid Cycle

The two successive oxidation and $CO_2$-releasing steps in the citric acid cycle, catalyzed by isocitrate dehydrogenase (yielding $\alpha$-ketoglutarate) and $\alpha$-ketoglutarate dehydrogenase (yielding succinyl-CoA).

$\alpha$-Ketoglutarate Dehydrogenase Complex

A mitochondrial multienzyme complex structurally and mechanistically homologous to PDH that oxidatively decarboxylates $\alpha$-ketoglutarate to succinyl-CoA and $CO_2$, using TPP, lipoic acid, CoA, FAD, and $NAD^+$ while being inhibited by high ATP and NADH.

Thiamine Pyrophosphate (TPP) Carbanion

The catalytically active dipolar ylide species formed on the thiazolium ring of TPP that performs a nucleophilic attack on the carbonyl carbon of an $\alpha$-keto acid, facilitating its decarboxylation in PDH and $\alpha$-ketoglutarate dehydrogenase.

Succinyl-CoA Synthetase

A citric acid cycle enzyme that couples the cleavage of the high-energy thioester bond in succinyl-CoA to the substrate-level phosphorylation of GDP to form GTP.

Succinate Dehydrogenase (Complex II)

An enzyme of the citric acid cycle that oxidizes succinate to fumarate while reducing FAD to $FADH_2$; uniquely among citric acid cycle enzymes, it is embedded directly in the inner mitochondrial membrane as part of the respiratory chain.

Fumarase

A citric acid cycle enzyme that catalyzes the reversible, stereospecific hydration of fumarate to produce L-malate.

Malate Dehydrogenase

The enzyme catalyzing the oxidation of L-malate to oxaloacetate with reduction of $NAD^+$ to $NADH$; driven forward under physiological conditions despite a positive standard free-energy change because its product, oxaloacetate, is rapidly removed by citrate synthase.

Net Yield of the Citric Acid Cycle

Per turn of the cycle oxidizing one acetyl CoA molecule, the products are $3\text{ NADH}$, $1\text{ FADH}_2$, $1\text{ GTP}$, and $2\text{ CO}_2$, yielding approximately $10.0\text{ ATP}$ equivalents (at $2.5\text{ ATP/NADH}$ and $1.5\text{ ATP/FADH}_2$).

Origin of Citric Acid Cycle $CO_2$ Carbons

Immediately following the first turn of the cycle, the two carbon atoms released as $CO_2$ originate from the oxaloacetate present at the start of that turn, not from the newly entered acetyl CoA.

Anaplerotic Reaction

A chemical reaction that replenishes intermediates of the citric acid cycle that have been siphoned off for biosynthetic pathways (e.g., pyruvate carboxylase generating oxaloacetate).

Inner Mitochondrial Membrane

The site of oxidative phosphorylation in eukaryotic cells; it is virtually impermeable to ions and polar molecules, requiring specific translocases and shuttle systems to transport metabolites across it.

Proton-Pumping Respiratory Complexes

Complexes I, III, and IV of the mitochondrial electron transport chain, which pump protons from the mitochondrial matrix into the intermembrane space to generate an electrochemical proton gradient.

Coenzyme Q (Ubiquinone)

A lipid-soluble quinone electron carrier that diffuses freely within the hydrophobic core of the inner mitochondrial membrane, shuttling electrons from Complexes I and II to Complex III.

Cytochrome c

A water-soluble heme-containing peripheral membrane protein in the intermembrane space that carries one electron at a time from Complex III to Complex IV.

Complex IV (Cytochrome c Oxidase)

The terminal complex of the electron transport chain that transfers electrons from reduced cytochrome c to molecular oxygen, reducing $O_2$ completely to two water molecules ($H_2O$) without releasing toxic partially reduced intermediates.

Rotenone

A specific inhibitor of respiratory Complex I that prevents electron transfer to ubiquinone, halting NADH oxidation through Complex I.

Antimycin A

An inhibitor of Complex III that blocks electron transfer to cytochrome c, causing upstream carriers ($NADH$ and $QH_2$) to accumulate in their reduced states.

Q Cycle

The cyclic mechanism in Complex III that resolves the transfer of electrons from a two-electron carrier ($QH_2$) to a one-electron acceptor (cytochrome c) while pumping protons into the intermembrane space.

Chemiosmotic Hypothesis

The principle that ATP synthesis is driven by the flow of protons back into the mitochondrial matrix down an electrochemical proton gradient through ATP synthase.

ATP Synthase $\beta$ Subunit Conformations

The three catalytic states of the $F_1$ $\beta$ subunit: Open (O, very low affinity for nucleotides), Loose (L, binds ADP and $P_i$), and Tight (T, binds ATP with high affinity and catalyzes ATP formation).

ATP Synthase $\gamma$ Subunit

The central asymmetric stalk of ATP synthase whose proton-flow-driven rotation sequentially alters the conformations of the three catalytic $\beta$ subunits between the Open, Loose, and Tight states.

Glycerol 3-Phosphate Shuttle

A fast cytosolic NADH shuttle that transfers electrons to mitochondrial FAD-linked glycerol 3-phosphate dehydrogenase, yielding approximately $1.5\text{ ATP}$ per cytosolic NADH.

Malate-Aspartate Shuttle

A cytosolic NADH shuttle that transfers electrons into the matrix to reform $NADH$, yielding approximately $2.5\text{ ATP}$ per cytosolic NADH.

Adenine Nucleotide Translocase

An inner mitochondrial membrane transport protein that exports $ATP$ out of the mitochondrial matrix in exchange for importing $ADP$.

Uncouplers

Molecules that make the inner mitochondrial membrane permeable to protons, collapsing the proton gradient and uncoupling electron transport from ATP synthesis; oxidation continues while ATP synthesis drops and energy is released as heat.

Glucose 6-Phosphatase

A liver endoplasmic reticulum enzyme that hydrolyzes glucose 6-phosphate to free glucose for release into the blood; defects in this enzyme result in chronic hypoglycemia.