Podcast
Questions and Answers
What is the primary function of the TCA cycle?
What is the primary function of the TCA cycle?
Which compound serves as the 2-C substrate for the TCA cycle?
Which compound serves as the 2-C substrate for the TCA cycle?
What role do anaplerotic reactions play in the TCA cycle?
What role do anaplerotic reactions play in the TCA cycle?
Which coenzyme is NOT required by the pyruvate dehydrogenase complex?
Which coenzyme is NOT required by the pyruvate dehydrogenase complex?
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Where does the TCA cycle primarily take place in eukaryotic cells?
Where does the TCA cycle primarily take place in eukaryotic cells?
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What condition is often associated with thiamine deficiency in alcoholics?
What condition is often associated with thiamine deficiency in alcoholics?
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Which of the following modifications regulates the PDH complex?
Which of the following modifications regulates the PDH complex?
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What is the most common biochemical cause of congenital lactic acidosis?
What is the most common biochemical cause of congenital lactic acidosis?
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Which element is known to activate the PDH enzyme, particularly in skeletal muscle?
Which element is known to activate the PDH enzyme, particularly in skeletal muscle?
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Which metabolite inhibits citrate synthase during the synthesis of citrate?
Which metabolite inhibits citrate synthase during the synthesis of citrate?
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What is a potential outcome of PDH deficiency in infants?
What is a potential outcome of PDH deficiency in infants?
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What dietary intervention might help some patients with PDH deficiency?
What dietary intervention might help some patients with PDH deficiency?
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What is a consequence of fumarase deficiency?
What is a consequence of fumarase deficiency?
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What is the primary role of aconitase in the TCA cycle?
What is the primary role of aconitase in the TCA cycle?
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Which enzyme is responsible for producing the first NADH in the TCA cycle?
Which enzyme is responsible for producing the first NADH in the TCA cycle?
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Which coenzymes are associated with the oxidative decarboxylation of α-ketoglutarate?
Which coenzymes are associated with the oxidative decarboxylation of α-ketoglutarate?
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What product is generated by the cleavage of succinyl coenzyme A?
What product is generated by the cleavage of succinyl coenzyme A?
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Which enzyme of the TCA cycle is embedded in the inner mitochondrial membrane?
Which enzyme of the TCA cycle is embedded in the inner mitochondrial membrane?
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What is the effect of ADP and Ca2+ on isocitrate dehydrogenase?
What is the effect of ADP and Ca2+ on isocitrate dehydrogenase?
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Which of the following substances inhibits α-ketoglutarate dehydrogenase?
Which of the following substances inhibits α-ketoglutarate dehydrogenase?
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Which statement is true regarding the TCA cycle?
Which statement is true regarding the TCA cycle?
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Study Notes
Tricarboxylic Acid Cycle (TCA) Overview
- Also known as the Citric Acid Cycle or Krebs Cycle
- A metabolic pathway crucial for energy production in most animals
- Oxidative catabolism of carbohydrates (CHO), amino acids (AAs), and fatty acids (FAs) converges here
- Converts carbon skeletons to carbon dioxide (CO₂)
Function of TCA
- Provides energy for ATP production in most animals
- Generates intermediates for various synthetic reactions
- Creates glucose from the carbon skeletons of some amino acids
- Synthesizes amino acids and heme
Other Important Features of TCA
- Anaplerotic reactions replenish intermediates in the pathway
- These reactions fill up the pathway by replenishing intermediates from the breakdown of amino acids
- Located in the mitochondria, close to the site of the electron transport chain (ETC)
- An oxygen-requiring pathway
Reactions of the TCA Cycle - Oxidative Decarboxylation of Pyruvate
- Acetyl CoA, a 2-carbon substrate, is generated from pyruvate, a 3-carbon compound
- Pyruvate must be transported from the cytosol to the mitochondrion
- The conversion is catalyzed by the pyruvate dehydrogenase complex, a multienzyme complex
- This step is critically important and significant
- Deficiencies in this complex can lead to serious central nervous system (CNS) problems
- Reduced ability of brain cells to produce ATP if the complex is inactive
- Wernicke-Korsakoff syndrome is one condition associated with thiamine deficiency, particularly in alcoholics
- This step is critically important and significant
Pyruvate Dehydrogenase Complex Coenzymes
- Requires five coenzymes:
- Thiamine pyrophosphate (TPP)
- Lipoic acid
- Coenzyme A
- Flavin adenine dinucleotide (FAD)
- Nicotinamide adenine dinucleotide (NAD)
Regulation of Pyruvate Dehydrogenase (PDH)
- PDH is covalently modified via phosphorylation/dephosphorylation
- Allosterically modified by ATP, acetyl CoA, and NADH
- These are "high-energy signals"
- High-energy signals switch the enzyme off
PDH Deficiency
- A rare condition—most common cause of congenital lactic acidosis
- Symptoms can include:
- Neurodegeneration, muscle spasticity, and early death in neonatal onset cases.
- No proven treatment exists
- Dietary restriction of CHO and supplementation with thiamine may be helpful
- One possible treatment is an experimental therapy using vitamins and supplements
- Arsenic poisoning inhibits enzymes needing lipoic acid as a coenzyme, interfering with PDH function
EMG and MRI findings in an example patient (Alex)
- EMG showed peripheral nerve damage in arms/legs
- MRI was clear
- Alex was in the ICU, showing symptoms of lactic acidosis—lactic acid in his blood reached dangerous levels
- PDH deficiency diagnosed
- Glucose drip replaced with a protein and lactate regimen.
- This was effective at stabilizing lactate levels
- Peripheral nerve damage occurred in infancy
- The treatment included a lifelong ketogenic diet
TCA Deficiency and Survival
- Defects in TCA cycle enzymes are rare
- This highlights the importance of the pathway for survival
- Fumarase Deficiency has resulted in:
- Encephalopathy, severe intellectual disabilities, unusual facial features, brain malformation, and epileptic seizures.
Synthesis of Citrate from Acetyl CoA and Oxaloacetate
- Catalyzed by Citrate Synthase
- Inhibited by citrate and substrate availability
- This is one example of metabolism of metabolites converting to other metabolites
Isomerization of Citrate By Aconitase
- Catalyzed by aconitase
- Inhibited by fluoracetate, a plant toxin used as a pesticide
- This enzyme is an important part of the cycle
Oxidative Decarboxylation of Isocitrate By Isocitrate Dehydrogenase
- Catalyzed by isocitrate dehydrogenase
- Produces the first NADH of the cycle
- Releases a carbon dioxide (CO₂) molecule
- Rate-limiting step
Oxidative Decarboxylation of α-Ketoglutarate By α-Ketoglutarate Dehydrogenase
- Releases the second CO₂
- Produces the second NADH of the cycle
- Uses TPP, Lipoic acid, FAD, NAD+, and CoA as coenzymes
- Inhibited by NADH and succinyl CoA and activated by Ca²+
- A-ketoglutarate is also produced from breakdown of amino acid glutamate
Cleavage of Succinyl Coenzyme A By Succinate Thiokinase
- Results in GTP production (substrate-level phosphorylation)
- Succinyl CoA can build up from propionyl CoA (FA metabolism)
Oxidation of Succinate By Succinate Dehydrogenase
- Produces FADH₂
- The only TCA cycle enzyme embedded in the inner mitochondrial membrane
- Functions as Complex II of the ETC
Hydration of Fumarate By Fumarase
- Produces L-malate
- Part of the Urea cycle, purine synthesis, and amino acid catabolism
Oxidation of Malate By Malate Dehydrogenase
- Produces the third NADH of the cycle.
- Produces oxaloacetate (OAA) via transamination of the amino acid aspartate
Energy Produced by TCA per cycle
- One turn of the cycle generates:
- 3 NADH
- 1 FADH2
- 1 GTP (equivalent to 1 ATP)
- 2 carbon dioxide molecules (CO₂)
- Therefore, 12 ATPs are made per cycle per acetyl CoA molecule oxidized
Regulation of TCA Cycle
- Some enzymes, such as citrate synthase, and isocitrate dehydrogenase are critically important
- These are all upregulated by low ATP to ADP ratios.
Role of TCA in Anabolism
- TCA intermediates serve as precursors for other biomolecules.
- The cycle provides building blocks for other necessary molecules such as amino acids, porphyrins, and heme
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