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TRICARBOXYLIC ACID CYCLE (TCA) / KREB'S CYCLE / CITRIC ACID CYCLE,…
TRICARBOXYLIC ACID CYCLE (TCA) / KREB'S CYCLE / CITRIC ACID CYCLE
Mitochondrial Matrix
Reversible reactions
Succinyl CoA <--> Succinate
Succinate <--> Fumarate
Citrate <--> Isocitrate/Aconitase
Fumarate <--> Malate
Amphibolic
Functions
Acetyl CoA catabolized by being oxidized
Substrate level phosphorylation
3NADH, 1 FADH2, GTP, ATP
Forms amino acid & lactate during starvation via transamination (anabolic) = gluconeogenesis
Enzymes of TCA Cycle
Citrate synthase
Condensation, Irreversible, Exergonic, Rate limiting step
Aconitase
Isomerization
Isocitrate dehydrogenase
Oxidative decarboxylation
a-KG dehydrogenase
Oxidative decarboxylation
Succinyl CoA synthase
Substrate Level Phosphorylation
Succinate dehydrogenase
Oxidation, reversible, endergonic
Fumarase
Hydration, reversible
Malate dehydrogenase
Oxidation, reversible, endergonic
Acetyl CoA
Common intermediate of carbohydrate, lipid, amino acid
Reactions of TCA Cycle
4. Oxidative decarboxylation of a-KG
Oxidative decarboxylation
a-ketoglutarate
a-ketoglutarate dehydrogenase / oxidoreductase
Succinyl CoA
5. Cleavage of Succinyl CoA to Succinate
Substrate Level Phosphorylation
Succinyl CoA
Succinyl CoA synthetase
Succinate / GTP / ATP
Endergonic, Reversible
3. Oxidative decarboxylation of Isocitrate
Oxidative decarboxylation
Isocitrate
Isocitrate dehydrogenase / oxidoreductase
a-ketoglutarate
6. Oxidation of Succinate to Fumarate
Oxidation
Succinate
Succinate dehydrogenase
Fumarate
Endergonic, Reversible
2. Isomerization of Citrate to Isocitrate
Isomerization
Citrate
Aconitase / Isomerase
Isocitrate
7. Hydration of Fumarate to Malate
Hydration
Fumarate
Fumarase
Malate
1. Synthesis of Citrate
Irreversible, Rate limiting Step, Exergonic
Condensation
Acetyl CoA & Oxaloacetate
Citrate synthase
Citrate
Citrate
Proceeds to FA synthesis
Accumulates in blood in pesticides with fluoroacetate
Inhibits PFK-1
8. Oxidation of Malate to Oxaloacetate
Reversible, Endergonic
Oxidation
Malate
Malate Dehydrogenase
Oxaloacetate & NADH
❤️ NICE TO KNOW ❤️
FAD / NAD+ = dehydrogenase
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Citrate, Isocitrate, Succinyl CoA, Succinate, Fumarate, Malate, Oxaloacetate
MAIS = Oxidative Enzymes
Malate DH, a-KG DH, Isocitrate, Succinate DH
ATP Calculation
Conversion
1 NADH = 2.5 ATP
1 FADH2 = 1.5 ATP
1 GTP = 1 ATP
ATP yield in TCA per 1 mol of Acetyl CoA = 10 ATP per TCA cycle
ATP Yield in Glycerol Phosphate Shuttle
Heart, Liver, Kidney
PDH = 5 ATP
TCA = 20 ATP
Glycolysis = 5 ATP
ATP Yield in Malate Aspartate Shuttle
Skeletal muscles, Brain
Glycolysis = 7 ATP
ATP Yield in Anaerobic PDH & TCA = 0
Since pyruvate --> lactate
Anaplerotic Reactions
Acetyl CoA cannot yield oxaloacetate
Replenish TCA intermediates
Amino acids converted to intermediates
Proline, Histidine, Arginine, Glutamine
Isoleucine, Threonine, Methionine, Valine
Phenylalanine, Tyrosine
Asparagine, Aspartate
Oxaloacetate
Fumarate
Succinyl CoA
a- ketoglutarate
Pyruvate carboxylase
Pyruvate --> Oxaloacetate
Liver, Brain, Adipose (not in muscles)
Major anaplerotic enzyme
Biotin
: required for CO2 fixation
Required in all carboxylation, except nucleotide metabolism
Regulatory Mechanisms
Succinyl CoA
: inhibits citrate synthase (rate limiting enzyme); only intermediate in TCA that can inhibit an enzyme
Isocitrate dehydrogenase
Allosteric
inhibitor
ATP / NADH
Allosteric
activator
ADP / NAD/ Calcium
a-ketoglutarate dehydrogenase
Allosteric
inhibitor
ATP / GTP / NADH
Succinyl CoA - negative feedback
Allosteric
activator
Calcium
Citrate synthase
Allosteric
inhibitor
ATP / NADH / Citrate
Succinyl CoA
Fatty acid chain
Allosteric
activator
Citrate / ADP / NAD / Calcium
Malate dehydrogenase
Allosteric
inhibitor
ATP / NADH
Pyruvate dehydrogenase
Allosteric
inhibitor
ATP / NADH / Acetyl CoA
Allosteric
activator
Calcium
Clinical Correlations
Suicide Substrates
Fluroacetate
toxin from plants
Activated to fluoroacetyl-CoA
Condenses to oxaloacetate to form fluorocetate
Inhibition of TCA by 2-fluorocitrate
Strong inhibitor of aconitase
Sodium fluoroacetate
Pesticide / Rodenticide
Toxic to aerobic organisms
Enters Kreb's and reacts with CoA = forms fluoroacetyl CoA
Citrate synthase
: converts fluoroacetyl CoA to fluorocitrate
Fluorocitrate binds to aconitase
Citrate fails to be converted to isocitrate
Leigh's Disease
Deficiency in Pyruvate dehydrogenase & a-KG dehydrogenase
Defective component: Dihydrolipoyl dehydrogenase (DLDH) - E3
Results to low energy
Neurologic deterioration / Brain & Muscle affected
Acidosis
Due to defective E3
Decrease oxidative decarboxylation of pyruvate
Decrease Acetyl CoA
Increase reduction of pyruvate to lactate
Hyperammonemia
a-KG used to detoxify ammonia
If withdrawn from TCA, it becomes glutamic acid
Catalyzed by glutamate dehydrogenase
Glutamic acid converted to glutamine
Glutamine synthetase
Low a-KG = Low TCA intermediates = loss of energy / consciousness
Ammonia inhibits a-ketoglutarate dehydrogenASE & pyruvate dehydrogenASE
Substrate
Product
Enzyme
Reaction
Substrate
Reaction
Enzyme
Product
Substrate
Enzyme
Product