Explore TCA Cycle Steps: Key Reactions for Cellular Energy

The tricarboxylic acid (TCA) cycle serves as a fundamental biochemical pathway for energy generation in aerobic organisms, functioning as both an energy conversion hub and a metabolic integrator. This cyclic pathway performs three essential biological roles: complete oxidation of acetyl groups to carbon dioxide, generation of high-energy electron carriers (NADH and FADH₂) for oxidative phosphorylation, and provision of critical intermediates for biosynthetic processes.

• Cellular localization: Mitochondrial matrix compartment in eukaryotes; cytoplasmic space in prokaryotic organisms.
• Primary substrate: Acetyl-CoA, derived from catabolism of carbohydrates, lipids, and amino acids.
• Cycle products: Per enzymatic turnover yields 3 NADH molecules, 1 FADH₂ molecule, 1 GTP molecule, and 2 CO₂ molecules.
• Multifunctional significance: Beyond its principal role in ATP synthesis through electron transport chain coupling, the cycle supplies carbon skeletons for amino acid synthesis and contributes to heme biosynthesis pathways.

Overview of all 8 chemical reactions of the TCA cycle and it's stoichiometry (Ryan DG et al., 2020).

The reaction steps are described in detail below:

1. Condensation of acetyl-CoA with oxaloacetate to form citric acid

This step is the initiating reaction of the TCA cycle, integrating the acetyl group into the cycle and providing the carbon skeleton for subsequent oxidation.

Reaction Mechanism and Enzymatic Details

Catalytic mechanism of citrate synthase

Order of substrate binding

Citrate synthase follows an "ordered concerted binding" mechanism:

• Oxaloacetate (OAA) binds first to the active site of the enzyme, inducing a conformational change to form a closed structure.
• Acetyl-CoA then enters the active site and its methyl carbon is nucleophilically attacked by the α-keto acid group of OAA to form the citoyl-CoA intermediate.
• Water molecules attack the thioester bond of citoyl-CoA, releasing CoA-SH and generating citric acid.

Key amino acid residues

• His274 and Asp375 are involved in proton transfer and stabilize the transition state.
• Arg329 immobilizes the carboxylic acid group of OAA through electrostatic interactions.

Structural features of the enzyme

• Dimeric structure: Citrate synthase exists as a homodimer, with two domains (large and small) per monomer, and undergoes a significant "hinge movement" (from open to closed state) upon substrate binding.
• X-ray crystallography reveals that in the closed state, the active site is completely enclosed, avoiding intermediate leakage and enhancing catalytic efficiency ("induced fit" model).

Fine Networks for Dynamic Regulation

Molecular details of metastable regulation

• Mechanism of ATP inhibition: ATP binds to the "metastable pocket" of the enzyme (away from the active site) and reduces the affinity of the enzyme for OAA through a conformational change (10-fold increase in Kd value).
• Competitive inhibition by NADH: NADH is structurally similar to OAA and competitively occupies the OAA binding site, blocking substrate entry.
• Feedback inhibition by succinyl-CoA: As a downstream product, succinyl-CoA binds directly to the CoA-SH release site, blocking CoA from leaving the active center.

Synergistic regulation

• Acetyl-CoA/OAA ratio: When acetyl-CoA is in excess (e.g., when fatty acid oxidation is active), the rate of OAA re-generation (via the backfill reaction) becomes the rate-limiting step of the cycle.
• NAD⁺/NADH ratio: High NADH (e.g., hypoxia) not only inhibits citrate synthase but also indirectly reduces TCA flux through inhibition of complex I (ETC).

Anaplerosis

The regeneration of oxaloacetate is essential to maintain the continuous operation of the TCA cycle, and the specific pathways include:

PC pathway

• Reaction: pyruvate + CO₂ + ATP → oxaloacetate + ADP + Pi
• Regulation: acetyl-CoA is a strong activator of PC (activates carboxylation to produce more OAA when acetyl-CoA builds up).
• Tissue specificity: active in liver and kidney, connects gluconeogenesis to the TCA cycle.

GOT pathway

• Reaction: aspartate + α-ketoglutarate ↔ oxaloacetate + glutamate
• Physiological significance: rapid replenishment of OAA via transamination reactions in cardiac and skeletal muscle to adapt to fluctuating energy demands.

PEPCK pathway

• Mitochondrial-type PEPCK: phosphoenolpyruvate (PEP) + CO₂ → oxaloacetate + GTP (reverse gluconeogenesis pathway).

Metabolic pathways for replenishing TCA cycle intermediates (Raja V et al., 2019).

2. Isomerization of citric acid to isocitric acid

This step prepares for subsequent oxidative decarboxylation by molecular rearrangement, which may seem simple but involves key structural transformations:

Molecular Mechanisms and Structural Biology Perspectives

Catalytic mechanism of aconitase

• Dehydration: the hydroxyl group (-OH) at the C2 position of citric acid is removed with the assistance of an iron-sulfur cluster (Fe-S) to form a cis-aconitate intermediate, releasing a water molecule.
• Hydration: the double bond at the C3 position of cis-aconitate is rehydroxylated by the attack of another molecule of water to form isocitric acid.

Stereochemical specificity

• Generation of only isocitric acid (and not the other isomers) is strictly controlled by the geometric configuration of the enzyme's active center.
• The reaction equilibrium is skewed towards citrate (~90% citrate vs 10% isocitrate), but the rapid consumption of isocitrate (catalyzed by IDH) drives the reaction forward.

Central role of iron-sulfur clusters (Fe-S)

• Active center structure: Contains a [4Fe-4S]²⁺ cluster in which three Fe atoms are coordinated to cysteine residues and the fourth Fe ("free Fe") is directly involved in substrate binding.
• Catalytic mechanism: Free Fe²⁺ acts as a Lewis acid, polarizing the hydroxyl oxygen of citric acid and facilitating proton transfer and dehydration. During dehydration and hydration, the oxidation state of the Fe-S cluster (Fe²⁺/Fe³⁺) changes dynamically and assists in stabilizing reaction intermediates.

Structural features of the enzyme

• Double structural domain conformation:
• N-terminal structural domain: contains Fe-S clusters and substrate binding pockets, responsible for catalytic activity.
• C-terminal domain: regulates conformational changes and ensures precise substrate targeting.
• Substrate channelization: Citric acid enters the active center through the Flexible Loop to avoid diffusion of the intermediate.

Dynamic regulation and physiological adaptation

Concentration regulation of substrate and product

• Citrate/isocitrate ratio: high isocitrate inhibits the reaction through mass action (but the actual effect is small because IDH rapidly consumes isocitrate).
• Metal ion dependence: Mg²⁺ or Mn²⁺ act as cofactors to stabilize substrate binding by neutralizing the negative charge of the phosphate group.

Redox sensitivity

• Superoxide radical (O₂-) destruction: Fe-S clusters are highly sensitive to oxidation, and O₂- can lead to cluster disintegration and release of free Fe²⁺ (triggering the Fenton reaction and exacerbating oxidative damage).
• Antioxidant defense mechanisms: Mitochondrial superoxide dismutase (SOD2) and glutathione (GSH) synergize to protect Fe-S cluster integrity.

Indirect regulation of energy status

• High ATP inhibits downstream IDH, leading to isocitrate accumulation and slight inhibition of aconitase activity (negative feedback regulation).

Dual function of aconitase

• Mitochondrial aconitase (ACO2): specializes in catalyzing TCA cycle reactions, no other known function.
• Cytoplasmic aconitase (IRP1): When cytosolic iron is sufficient, IRP1 assembles Fe-S clusters and loses RNA binding capacity. When iron-deficient, IRP1 loses Fe-S clusters and is converted to Iron Regulatory Protein (IRP), which binds to Iron Response Elements (IREs) and regulates gene expression: inhibits Ferritin translation (reduces iron storage). Stabilizes Transferrin Receptor (TfR) mRNA (increases iron uptake).

3. Oxidative decarboxylation of isocitric acid to α-ketoglutarate

This step is the key oxidative decarboxylation reaction for the first production of NADH and CO₂ in the TCA cycle and is a central regulatory point for metabolic fluxes.

Molecular Mechanism and Enzymatic Details

Classification and structure of isocitrate dehydrogenase (IDH)

Family of isoenzymes

• IDH1: cytoplasmic type, NADP⁺ dependent, mainly involved in antioxidant (NADPH generation) and lipid synthesis.
• IDH2: Mitochondrial type, NADP⁺-dependent, function similar to IDH1 but localized to mitochondria.
• IDH3: Mitochondrial type, NAD⁺ dependent, specialized in TCA cycle, heterotetramer (α₂βγ), directly involved in energy metabolism.

Active Center Characteristics

• The α subunit of IDH3 contains an isocitrate binding site and a NAD⁺ binding domain.
• The β and γ subunits are involved in metabolic regulation (e.g. ADP/ATP binding).

Chemical mechanism of catalytic steps

Oxidative dehydrogenation

• The hydroxyl group at the C2 position of isocitric acid is oxidized to a keto group, generating oxalosuccinate (unstable β-keto acid intermediate), while NAD⁺ is reduced to NADH.
• Metal ion dependence: requires Mg²⁺ or Mn²⁺ to stabilize the transition state (e.g., neutralize the negative charge of the phosphate group).

Decarboxylation reaction

• Oxalysuccinic acid is spontaneously decarboxylated to form α-ketoglutarate (α-KG), releasing CO₂.
• The decarboxylation process is accomplished via an enolization intermediate of β-keto acids without additional enzyme catalysis.

Stereochemical specificity

• Catalyzes the oxidation of isocitric acid only (and not other citric acid isomers), determined by the precise spatial configuration of the active center.

Dynamic Regulation and Energy Sensing

Molecular Mechanisms of Metamorphic Regulation

• Activation by ADP: ADP binds to the β-subunit of IDH3, inducing a conformational change that enhances the enzyme's affinity for isocitrate (10-fold decrease in Km value).
• Inhibitory effect of ATP/NADH: ATP competitively binds to the ADP site, blocking the activation effect. NADH directly reduces enzyme activity through product inhibition (high NADH/NAD⁺ ratio inhibits the reaction).

Co-regulation by calcium ions (Ca²⁺)

• In muscle and nerve cells, Ca²⁺ enhances enzyme activity by binding to the γ subunit of IDH3 in rapid response to energy demands (e.g., muscle contraction or synaptic transmission).

Rate-limiting effect of substrate concentration

• Isocitrate levels are regulated by upstream aconitase activity, and the mitochondrial NAD⁺/NADH ratio directly affects the direction of the response.

Metabolic Integration and Biological Function

Connecting Carbon and Nitrogen Metabolism

• TCA cycle intermediate: α-KG enters subsequent steps to generate succinyl-CoA.
• Amino acid metabolism hub: α-KG generates glutamate (Glu) via transamination reaction, involved in ammonia detoxification and protein synthesis.

Nitrogen homeostasis regulation

• Glutamate dehydrogenase (GDH) catalyzes α-KG + NH₃ + NADPH ↔ Glu + NADP⁺, regulating free ammonia levels.

Epigenetic regulation

• α-KG is an essential cofactor for dioxygenases (e.g., histone demethylases, DNA demethylases) and affects chromatin modification and gene expression.
• Cancer association: IDH mutations lead to aberrant metabolism of α-KG to 2-hydroxyglutarate (2-HG), which competitively inhibits dioxygenases and triggers epigenetic disorders.

Antioxidant defense

• IDH1/2 resists oxidative stress by generating NADPH and maintaining the reduced state of glutathione (GSH).

4. Oxidative Decarboxylation of α-Ketoglutarate to Succinyl-CoA

This reaction represents the TCA cycle's second oxidative decarboxylation event and serves as a critical regulatory node for cellular energy metabolism.

Catalytic Machinery

The α-ketoglutarate dehydrogenase multienzyme complex (α-KGDH) shares structural and functional homology with pyruvate dehydrogenase, comprising three coordinated subunits:

• E1 (α-Ketoglutarate Decarboxylase): Utilizes thiamine pyrophosphate (TPP) to decarboxylate α-ketoglutarate, forming a succinyl-semialdehyde-TPP intermediate.
• E2 (Dihydrolipoyl Transsuccinylase): Catalyzes transfer of the succinyl group to CoA via a lipoamide prosthetic group, generating the energy-rich thioester bond in succinyl-CoA.
• E3 (Dihydrolipoyl Dehydrogenase): Reoxidizes reduced lipoamide using FAD, ultimately transferring electrons to NAD⁺ for NADH production.

Cofactor Synergy

• TPP: Stabilizes reactive intermediates during decarboxylation.
• Lipoic acid: Functions as a swinging arm to shuttle intermediates between active sites.
• CoA-SH: Terminates the reaction by capturing the succinyl group.
• FAD/NAD⁺: Serve as terminal electron acceptors, linking the reaction to oxidative phosphorylation.

Regulatory Hierarchy

• Inhibition: Succinyl-CoA (product feedback) and NADH (redox sensing) suppress activity.
• Activation: Calcium ions (Ca²⁺) enhance catalytic efficiency in excitable tissues.
• Energy-State Sensing: Elevated ATP/ADP ratios reduce flux through this step, coordinating TCA activity with cellular energy demands.
• Substrate Channeling: The lipoamide arm minimizes diffusion of reactive intermediates, ensuring reaction fidelity.

Metabolic Integration

• Nitrogen Metabolism Interface: α-Ketoglutarate bridges carbon and nitrogen cycles via glutamate biosynthesis.
• Oncogenic Metabolism: Cancer cells exploit glutaminolysis to generate α-ketoglutarate, supporting biomass production (Warburg effect).
• Heme Synthesis: Succinyl-CoA combines with glycine to initiate porphyrin biosynthesis.
• Ketogenesis Regulation: Hepatic succinyl-CoA activates HMG-CoA synthase, a rate-limiting enzyme in ketone body production.
• Redox Homeostasis: NADH generated here sustains mitochondrial NAD⁺/NADH balance, crucial for ETC function.

5. Succinyl-CoA to Succinate Conversion

This reaction represents the sole instance of substrate-level phosphorylation in the citric acid cycle, directly generating high-energy phosphate bonds through enzymatic catalysis rather than electron transport chain (ETC)-dependent processes.

Mechanistic Overview

Enzyme Classification

• SCS-GTP (animals): Catalyzes guanosine triphosphate (GTP) synthesis via GDP phosphorylation.
• SCS-ATP (plants/bacteria): Mediates adenosine triphosphate (ATP) production from ADP.

Structural Organization

Composed of α and β subunits forming a heterodimer

• α-subunit: Binds succinyl-CoA and contains a phosphorylatable histidine residue (His246).
• β-subunit: Facilitates nucleotide binding (GDP/ADP) and phosphate transfer.

Catalytic Process

• Thioester Cleavage: Reaction initiates with thioester bond hydrolysis in succinyl-CoA, releasing CoA-SH and forming a phosphohistidine intermediate (His246 phosphorylation).
• Phosphotransfer: The high-energy phosphate group transfers to GDP/ADP, yielding GTP/ATP and succinate.
• Cofactor Role: Mg²⁺ stabilizes nucleotide interactions and optimizes phosphotransfer efficiency.

Stereoselectivity

Exclusive catalysis of the L-succinyl-CoA isomer, governed by geometric constraints in the enzyme's active site.

Bioenergetic Significance

• Substrate-Level Phosphorylation: Directly couples chemical energy from thioester cleavage to nucleotide phosphorylation, independent of proton gradients or ETC components.
• Efficiency Constraints: Produces 1 GTP/ATP per cycle versus ~10 ATP equivalents per NADH via oxidative phosphorylation.
• Physiological Relevance: Provides emergency ATP synthesis during hypoxia/ischemia when ETC function is compromised.

Nucleotide Specialization

• Animal Systems: GTP supports translation elongation (EF-Tu), G-protein signaling, and gluconeogenesis (PEP carboxykinase), with interconversion to ATP via nucleoside diphosphate kinase.
• Plant/Microbial Systems: Direct ATP production fuels photosynthetic carbon fixation or biosynthetic pathways.

Metabolic Network Integration

Succinyl-CoA Sources

• Core Pathway: α-Ketoglutarate dehydrogenase-mediated oxidative decarboxylation.
• Amino Acid Catabolism: Valine/isoleucine degradation.
• Lipid Metabolism: Propionyl-CoA conversion via methylmalonyl-CoA in odd-chain fatty acid β-oxidation.

Succinate Utilization

• Cycle Continuation: Oxidation to fumarate by succinate dehydrogenase (Complex II), yielding FADH₂.
• Heme Biosynthesis: Condensation with glycine to form δ-aminolevulinic acid (ALA).
• Ketogenesis: Hepatic succinyl-CoA activates HMG-CoA synthase, driving ketone body production.
• Succinate Signaling:Acts as an extracellular ligand for GPR91, modulating blood pressure, inflammatory responses, and hypoxia adaptation through receptor activation.

6. Succinate Oxidation to Fumarate

This reaction serves as the exclusive interface between the TCA cycle and mitochondrial electron transport, enabling direct coupling of metabolic flux with energy transduction.

Catalytic Architecture

Succinate Dehydrogenase (SDH) Complex Structure

• SdhA (Flavoprotein subunit): Binds FAD cofactor to oxidize succinate, initiating electron transfer.
• SdhB (Iron-sulfur subunit): Contains [2Fe-2S], [4Fe-4S], and [3Fe-4S] clusters for sequential electron shuttling.
• SdhC/SdhD (Membrane anchor): Embeds in the inner mitochondrial membrane, transfers electrons to ubiquinone (CoQ), and stabilizes heme b for redox tuning.
• Cofactor Synergy: FAD-mediated dehydrogenation, Fe-S-mediated electron relay, and heme b-assisted charge stabilization.
• Unique Localization: As the sole TCA enzyme integrated into the respiratory chain, SDH (Complex II) physically links substrate oxidation with oxidative phosphorylation.

Reaction Dynamics

• Dehydrogenation: Stereospecific removal of two hydrogens from succinate's C1 and C2 generates fumarate (trans-configuration) while reducing FAD to FADH₂.
• Electron Routing: FADH₂ electrons traverse Fe-S clusters to reduce CoQ, forming ubiquinol (UQH₂). Indirect proton gradient contribution via subsequent Complex III activity.
• Stereochemical Fidelity: Exclusive production of trans-fumarate prevents metabolic interference from cis-isomers.

Bioenergetic Implications

• FADH₂ Yield: Generates ~1.5 ATP equivalents via UQH₂-mediated proton pumping, contrasting with NADH's ~2.5 ATP output.
• Hypoxic Adaptation: Maintains basal ATP synthesis when Complex I is inoperative.
• Reverse Electron Transfer (RET): Elevated succinate drives electrons backward through Complex I, producing pathological ROS during ischemia-reperfusion.

Regulatory Landscape

• Substrate-Driven Activation: High succinate concentrations promote forward flux.
• Malonate Inhibition: Structural analog (Ki ≈0.1 mM) competitively blocks SDH active site, used experimentally to arrest TCA cycling.
• Energy-State Modulation: Hypoxia-induced UQH₂ accumulation feedback-inhibits SDH. Elevated ATP/ADP ratios suppress overall electron transport flux.

Metabolic Integration

Succinate Sources

• Core Pathway: Succinyl-CoA conversion by succinyl-CoA synthetase.
• Amino Acid Catabolism: Valine/isoleucine degradation.
• GABA Shunt: Neurotransmitter-derived succinate via GABA transaminase.

Succinate Fate

• Cycle Continuation: Fumarate production for subsequent TCA steps.
• Anabolic Precursor: δ-Aminolevulinic acid synthesis for heme biosynthesis.
• Gluconeogenic Link: Oxaloacetate generation via malate shuttle.

Signaling Roles

• Hypoxic Reprogramming: Inhibits PHD enzymes to stabilize HIF-1α, driving angiogenesis in tumors.
• Inflammatory Modulation: Activates GPR91 receptor, potentiating IL-1β release in macrophages.
• Epigenetic Influence: Suppresses histone demethylases (e.g., KDM5), altering chromatin accessibility.

7. Hydrogenation of Malic Acid from Ferulic Acid

This step is the only hydration reaction in the TCA cycle, and it appears to be a simple one, but it is characterized by sophisticated stereochemical control and metabolic integration.

Molecular Mechanism and Enzymatic Details

Catalytic Properties of Fumarase

Stereospecificity:

• Catalyzes only the hydration of fumaric acid (trans-double bond) to L-malate (not D-malate), determined by the precise spatial configuration of the active center.
• The reaction occurs via a trans addition mechanism whereby water molecules attack the C2 and C3 positions of the fenugreek to form a single stereoisomer.

Two isoforms:

• Mitochondrial type Fumarase (FH): participates in the TCA cycle and is localized in the mitochondrial matrix.
• Cytoplasmic-type Fumarase (FUM1): function unknown, possibly related to DNA repair.

Catalytic mechanism

• Substrate binding and activation: The fumaric acid is directed into the active center by electrostatic interactions (binding to Arg140, Lys324) and the double bond is polarized.
• Water molecule attack: Water molecules, assisted by Glu331, add to the C2 and C3 positions in a trans manner to form the intermediate enolated malic acid.
• Proton rearrangement: Proton transfer (His129 is involved) produces stabilized L-malic acid.

Thermodynamic and kinetic properties

• Equilibrium favors hydration: ΔG°≈ -3.8 kJ/mol, and the reaction tends to produce malic acid under physiological conditions.
• High catalytic efficiency: kcat≈ 800 s-¹, ensuring high speed of TCA cycle.

Metabolic integration and physiological function

Connecting the TCA cycle with gluconeogenesis

• Malate can enter the cytoplasm through the mitochondria-cytoplasmic shuttle (malate-aspartate shuttle) and be converted to pyruvate by malic enzyme to participate in gluconeogenesis or lipid synthesis.

Redox balance

• Malate acts as an indirect carrier of NADH, transferring reducing equivalents from the mitochondria to the cytoplasm via a shuttle system to support NADH-requiring processes such as lipid synthesis.

Paracrine metabolism of fenugreek

• Urea cycle: fenugreek can be generated by arginine succinate lyase, linking nitrogen and carbon metabolism.
• Purine synthesis: fenugreek is involved in the synthesis of IMP (hypoxanthine nucleotides).

8. Oxidation of malic acid to regenerate oxaloacetate

This step is the final reaction of the TCA cycle and the key node connecting gluconeogenesis to energy metabolism.

Molecular Mechanism and Enzymatic Details

Classification and structure of malate dehydrogenase (MDH)

• Mitochondrial MDH (mMDH): participates in the TCA cycle with NAD⁺ as a cofactor.
• Cytoplasmic MDH (cMDH): participates in the malate-aspartate shuttle with NAD⁺ or NADP⁺ as cofactor.

• Active Center Characterization: Contains a conserved Ser-Asp-Lys catalytic triad responsible for proton transfer and redox reactions.

Catalytic mechanism

• Malate dehydrogenation: The hydroxyl group at the C2 position of malate is oxidized to a keto group, producing oxaloacetate, while NAD⁺ is reduced to NADH.
• Transition state stabilization: Mg²⁺ or Mn²⁺ binds the β-keto acid group of oxaloacetate, preventing decarboxylation and stabilizing the product.

Thermodynamic challenge and metabolic drive

• ΔG° ≈ +30 kJ/mol: the reaction proceeds strongly in the reverse direction (favoring malate production) under standard conditions.
• Rapid consumption of oxaloacetate: Condensation with acetyl-CoA to produce citric acid (catalyzed by citrate synthase). Participation in gluconeogenesis (conversion to phosphoenolpyruvate).
• Re-oxidation of NADH: Rapid consumption of NADH via the electron transport chain (ETC) to maintain a low NADH/NAD⁺ ratio.

Metabolic regulation and dynamic equilibrium

Substrate concentration driven

• High malate concentrations (e.g., mitochondrial malate accumulation) drive the reaction in a positive direction.

Metabolic regulation

• ATP inhibition: high ATP inhibits mMDH activity and coordinates TCA cycling and energy states.
• Citric acid activation: citric acid enhances the affinity of mMDH for malate through a metabolic effect.

Metabolite Channeling

• Oxaloacetate is "captured" by citrate synthase, forming an enzyme-enzyme complex (physical coupling of MDH and citrate synthase) to avoid diffusion of intermediates.

Metabolic integration and biological function

Core nodes of gluconeogenesis

• Mitochondrial oxaloacetate: Enters the cytoplasm via the malate-aspartate shuttle and is converted to PEP by PEP carboxykinase to initiate gluconeogenesis.
• Hepatocyte adaptation: upregulation of MDH activity in fasting state supports gluconeogenesis.

Redox shuttle system

• Malate-aspartate shuttle: Transfers reducing equivalents of cytoplasmic NADH to mitochondria (generates NADH), supports oxidative phosphorylation.

Amino acid metabolism crossover

• Oxaloacetate generates aspartate via transamination reactions, which are involved in the urea cycle and nucleotide synthesis.

References

1. Arnold PK, Finley LWS. "Regulation and function of the mammalian tricarboxylic acid cycle." J Biol Chem. 2023;299(2):102838. doi: 10.1016/j.jbc.2022.102838
2. Wu J, Liu N, Chen J, Tao Q, Li Q, Li J, Chen X, Peng C. "The Tricarboxylic Acid Cycle Metabolites for Cancer: Friend or Enemy." Research (Wash D C). 2024 ;7:0351. doi: 10.34133/research.0351