BB ch 16, p1

Citrate synthase

Enzyme that catalyzes the condensation of acetyl-CoA and oxaloacetate to form citrate; highly exergonic and essentially irreversible.

Aconitase

Iron–sulfur enzyme that isomerizes citrate to isocitrate via the intermediate cis-aconitate.

Isocitrate dehydrogenase

Enzyme that oxidatively decarboxylates isocitrate to α-ketoglutarate, producing CO₂ and NADH (or NADPH).

α-Ketoglutarate dehydrogenase complex

Multienzyme complex that converts α-ketoglutarate to succinyl-CoA and CO₂, generating NADH; mechanistically similar to PDH.

Succinyl-CoA synthetase

Enzyme that performs substrate-level phosphorylation, converting succinyl-CoA to succinate and forming GTP (or ATP).

Succinate dehydrogenase

Membrane-bound flavoprotein that oxidizes succinate to fumarate, reducing FAD to FADH₂.

Fumarase

Highly stereospecific enzyme that hydrates fumarate to L-malate.

Malate dehydrogenase

Enzyme that oxidizes L-malate to oxaloacetate, producing NADH despite a large positive ΔG'°.

Pyruvate dehydrogenase complex (PDH)

Noncovalent assembly of three enzymes that oxidatively decarboxylates pyruvate to acetyl-CoA; requires five coenzymes.

Acetyl-CoA

Two-carbon thioester produced from pyruvate; entry substrate for the TCA cycle.

Oxaloacetate (OAA)

Four-carbon dicarboxylic acid that condenses with acetyl-CoA and is regenerated at cycle’s end.

Citrate

Six-carbon tricarboxylic acid formed in step 1; symmetric but reacts asymmetrically in the cycle.

Cis-aconitate

Unsaturated intermediate formed during the dehydration part of the aconitase reaction.

Isocitrate

Rearranged product of citrate isomerization; substrate for isocitrate dehydrogenase.

α-Ketoglutarate

Five-carbon α-keto acid produced from isocitrate; undergoes a second oxidative decarboxylation.

Succinyl-CoA

Four-carbon thioester formed from α-ketoglutarate; high-energy compound used for substrate-level phosphorylation.

Succinate

Four-carbon dicarboxylate produced from succinyl-CoA; substrate for succinate dehydrogenase.

Fumarate

Trans-dicarboxylate product of succinate oxidation; hydrated to L-malate.

L-Malate

Hydration product of fumarate; oxidized to regenerate oxaloacetate.

β-Cleavage strategy

Chemical logic of condensing acetate with OAA so that a β-cleavage can release energy as CO₂.

Oxidative decarboxylation

Reaction type combining oxidation with removal of CO₂, yielding reduced coenzyme (NADH).

NADH

Reduced nicotinamide coenzyme that donates electrons to the electron transport chain for ATP production.

FADH₂

Reduced flavin coenzyme generated by succinate dehydrogenase; feeds electrons into the respiratory chain.

GTP

Nucleoside triphosphate formed by succinyl-CoA synthetase; readily converted to ATP.

NAD⁺

Oxidized form of nicotinamide coenzyme that accepts a hydride ion in many dehydrogenase reactions.

FAD

Oxidized flavin coenzyme capable of one- or two-electron transfers; bound to flavoproteins.

TPP (Thiamine pyrophosphate)

Coenzyme derived from vitamin B₁; stabilizes carbanions during α-keto acid decarboxylation.

Thiamine pyrophosphate

Full name of TPP, the coenzyme used by PDH and α-ketoglutarate dehydrogenase.

Lipoic acid

Swinging arm coenzyme that couples acyl-group and electron transfer in PDH and α-KG DH.

Coenzyme A (CoA-SH)

Coenzyme containing β-mercaptoethylamine and pantothenic acid; carries acyl groups as thioesters.

Nicotinamide coenzymes

Collective term for NAD⁺/NADH and NADP⁺/NADPH that mediate two-electron hydride transfers.

Flavin coenzymes

Group including FAD/FADH₂ that can participate in one- and two-electron transfers.

Electron transport chain

Mitochondrial inner-membrane pathway where NADH and FADH₂ are re-oxidized, driving ATP synthesis.

Oxidative phosphorylation

Coupling of electron transport to ATP formation via a proton gradient across the inner mitochondrial membrane.

Hans Krebs

Scientist who elucidated the cyclic pathway for acetate oxidation, now called the Krebs cycle.

Citric Acid Cycle

Eight-step cyclic pathway that oxidizes acetyl-CoA to CO₂ while capturing energy in NADH, FADH₂, and GTP.

Krebs cycle

Synonym for the Citric Acid Cycle, honoring Hans Krebs.

TCA cycle

Abbreviation for tricarboxylic acid cycle; another name for the Citric Acid Cycle.

Acetyl group transfer

Movement of a two-carbon unit from CoA to another molecule, as in citrate synthesis.

Hydride transfer

Movement of a hydride ion (H⁻) to or from NAD⁺/NADP⁺ during dehydrogenase reactions.

Oxalosuccinate

β-keto acid intermediate of isocitrate oxidation that rapidly decarboxylates to α-ketoglutarate.

Carbanion transition state

Intermediate stabilized by Mn²⁺ in isocitrate dehydrogenase during decarboxylation.

Malonate

Structural analog of succinate that competitively inhibits succinate dehydrogenase, halting the cycle.

Anaplerotic reactions

"Filling-up" reactions that replenish TCA intermediates withdrawn for biosynthesis.

Prochiral molecule

Molecule like citrate that is achiral yet can be converted into chiral products by an enzyme.

Iron–sulfur center

4Fe–4S cluster in aconitase that binds citrate and facilitates dehydration/rehydration.

ATP

Main cellular energy currency produced indirectly by TCA-generated NADH and FADH₂.

Substrate-level phosphorylation

Direct formation of ATP or GTP from a phosphorylated intermediate, as in the succinyl-CoA synthetase step.

Reactive thiol group

–SH moiety of CoA that forms high-energy thioesters with acyl groups.

Ferris wheel metaphor

Illustration describing the cyclic, continuous nature of the TCA cycle generating energy.

Aerobic conditions

Presence of oxygen, allowing pyruvate to be fully oxidized via PDH and the TCA cycle.

Acetate oxidation

Overall conversion of two-carbon acetyl units to two molecules of CO₂ in the cycle.

24-electron oxidation

Total number of electrons removed during complete glucose oxidation to CO₂.

Cellular respiration Stage 1

Oxidation of fuels to acetyl-CoA, including glycolysis and β-oxidation.

Cellular respiration Stage 2

Oxidation of acetyl-CoA in the TCA cycle, producing reduced coenzymes and some ATP/GTP.

Cellular respiration Stage 3

Electron transport and oxidative phosphorylation generating the bulk of ATP.

β-Mercaptoethylamine

Component of CoA that contains the reactive thiol group.

Pantothenic acid

Vitamin component of coenzyme A linking the adenosine and β-mercaptoethylamine portions.

E1 enzyme

Pyruvate dehydrogenase component of PDH that uses TPP for decarboxylation.

E2 enzyme

Dihydrolipoyl transacetylase within PDH that transfers the acetyl group to CoA.

E3 enzyme

Dihydrolipoyl dehydrogenase in PDH that regenerates oxidized lipoamide using FAD and NAD⁺.

Dihydrolipoyl transacetylase

E2 component of PDH and α-KG DH that carries lipoic acid and swings acyl groups to CoA.

Dihydrolipoyl dehydrogenase

E3 component using FAD and NAD⁺ to re-oxidize reduced lipoamide.

α-Keto acid decarboxylation

Removal of CO₂ from α-keto acids, catalyzed by TPP-dependent enzymes.

Hydration reaction

Addition of water across a double bond, as in the fumarase step.

Dehydration reaction

Removal of water to create a double bond, initial part of aconitase’s mechanism.

Condensation reaction

Combination of two substrates to form a larger molecule, e.g., acetyl-CoA + OAA → citrate.

Decarboxylation reaction

Release of CO₂ during oxidation of isocitrate and α-ketoglutarate.

ΔG'° negative steps

Reactions with large negative free energy making them essentially irreversible (steps 1, 3, 4).

ΔG'° positive steps

Reactions driven forward in vivo by product removal, e.g., malate dehydrogenase.

Citrate symmetry

Citrate is symmetric but enzymes treat its two ends differently due to specific binding.

Asymmetric reaction

Process where a symmetric molecule reacts in an oriented manner, leading to selective product formation.

Ordered reaction sequence

Mechanism where oxaloacetate binds citrate synthase first, enabling acetyl-CoA binding.

Conformational change

Structural shift in an enzyme, such as domain closure in citrate synthase upon ligand binding.

Mitochondrial matrix

Location of the TCA cycle and PDH complex within eukaryotic cells.

Pyruvate transport

Movement of pyruvate from cytosol into mitochondria before oxidative decarboxylation.

Pyruvate oxidation energy capture

Energy from pyruvate decarboxylation conserved as NADH and thioester of acetyl-CoA.

CO₂ production

Release of two carbon dioxide molecules per turn of the TCA cycle.

Cycle regeneration

Restoration of oxaloacetate at the end of each turn, allowing continuous operation.

Oxaloacetate regeneration

Final step where malate is oxidized to OAA, completing the cycle.

Biosynthetic intermediates

TCA components that serve as precursors for amino acids, nucleotides, and other compounds.

Regulation of TCA cycle

Control via irreversible steps, substrate availability, and product inhibition.

Mn²⁺ role

Metal ion that stabilizes intermediates in isocitrate dehydrogenase, facilitating decarboxylation.

Aconitase active site

Pocket with specific binding points that distinguishes the prochiral arms of citrate.

Succinyl phosphate

High-energy intermediate formed during succinyl-CoA synthetase reaction before phosphohistidine.

Phosphohistidine intermediate

Covalent phosphoryl-enzyme species that donates phosphate to GDP.

GDP phosphorylation

Transfer of phosphate from phosphohistidine to GDP forming GTP.

Energy yield per turn

3 NADH, 1 FADH₂, 1 GTP/ATP, and 2 CO₂ molecules generated per cycle rotation.

3 NADH per turn

Number of NADH molecules produced in one cycle round (steps 3, 4, and 8).

1 FADH₂ per turn

Number of FADH₂ molecules formed in the succinate dehydrogenase step.

1 GTP per turn

Nucleoside triphosphate generated by succinyl-CoA synthetase.

2 CO₂ per turn

Carbon atoms from acetyl-CoA fully oxidized and released as carbon dioxide.

Eight enzymatic steps

Total number of distinct reactions comprising the TCA cycle.

Steps 1, 3, 4 irreversible

Key regulatory points in the cycle with large negative ΔG'° values.

Malate oxidation ΔG'° +29.7

Standard free energy for L-malate → OAA, driven forward in vivo by low OAA concentration.

Citrate synthase ΔG'° −32.2

Strongly negative free energy that pulls the cycle forward during citrate formation.

Succinate dehydrogenase membrane-bound

Only TCA enzyme located in the inner mitochondrial membrane, linking to ETC complex II.

Malonate competitive inhibitor

Dicarboxylate that mimics succinate, inhibiting succinate dehydrogenase.

Aerobic oxidation of glucose

Complete breakdown yielding CO₂, water, and ATP via glycolysis, PDH, TCA, and oxidative phosphorylation.

Filling up reactions

Same as anaplerotic reactions; restore TCA intermediate pools.