Function
Citrate Synthesis
The enzyme citrate synthase catalyzes the formation of citrate from acetyl CoA and oxaloacetate, often regarded as the first step of the TCA cycle. This reaction is virtually irreversible and has a delta-G-prime of -7.7 Kcal/M, strongly favoring citrate formation. The availability of substrates and products regulates the activity of citrate synthase. For instance, citrate is an inhibitor of citrate synthase, while oxaloacetate’s binding increases its affinity for acetyl-CoA. It mentions that phosphofructokinase-1 in glycolysis is inhibited by citrate, which activates acetyl-CoA carboxylase for fatty acid synthesis. This point illustrates the interconnectivity of our metabolic cycles.[5]
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Isomerization of Citrate
The enzyme aconitase catalyzes the reversible conversion of citrate to isocitrate, which contains an iron-sulfur center that facilitates the hydroxyl group migration. Cis-aconitate is the intermediate product of this reaction.[6]
Oxidative Decarboxylation of Isocitrate
The oxidative decarboxylation of isocitrate to alpha-ketoglutarate becomes catalyzed by NAD+ -dependent isocitrate dehydrogenase, producing CO2, NADH, and a proton; this is the rate-limiting step of the TCA cycle. The first reduced coenzyme production in the cycle occurs at this reaction. The tendency of this reaction to produce gas makes it irreversible. ADP and calcium ions allosterically regulate isocitrate dehydrogenase by activating it, while ATP and NADH inhibit its activity.[7]
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Oxidative Decarboxylation of Alpha-ketoglutarate
The conversion of alpha-ketoglutarate to succinyl-CoA is catalyzed by the alpha-ketoglutarate dehydrogenase complex producing NADH, CO2, and H+. The function of the alpha-ketoglutarate dehydrogenase complex is analogous to PDC. Alpha-ketoglutarate becomes decarboxylated by E1 of this complex, transferring the 4 remaining carbons to thiamine pyrophosphate. Thiamine pyrophosphate is the first cofactor. Then, the succinyl group is transferred to CoASH by E2 with the help of FAD. The final step involves the resynthesis of FAD and NADH from NAD+ by E3. This last step ensures the maintenance of substrates and cofactors required to continue the dehydrogenase complex activity. The cofactors necessary for alpha-ketoglutarate dehydrogenase complex include thiamine pyrophosphate, lipoic acid, coenzyme A, NAD+, and FAD. Succinyl-CoA, NADH, and ATP inhibit the alpha-ketoglutarate dehydrogenase complex.[8][9]
Cleavage of Succinyl Coenzyme A
The enzyme succinate thiokinase catalyzes the reversible interconversion of succinyl-CoA to succinate by cleaving succinyl CoA’s thioester bond. The enzyme uses inorganic phosphate and dinucleotide to produce trinucleotide and CoA. This coupled reaction is called substrate-level phosphorylation, like in glycolysis.[10]
Oxidation of Succinate
Succinate dehydrogenase is also called complex II due to its role in the aerobic respiration chain. It catalyzes the reduction of ubiquinone to ubiquinol. The TCA cycle catalyzes the oxidation of succinate to fumarate, producing a reduced FADH2 from FAD.[11]
Hydration of Fumarate
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Fumarate (or fumarate hydratase) catalyzes the reversible hydration to malate hydration. In another attempt to illustrate the interconnectedness of metabolic pathways, note that fumarate production also occurs in the urea cycle.[12]
Oxidation of Malate
Malate dehydrogenase is the catalyst in the reversible oxidation of malate to oxaloacetate, which is the last step of the TCA cycle. This enzyme plays a crucial role in NADH oxidation within the TCA cycle. The delta-G-prime is positive, which indicates that the reaction favors malate. However, consuming oxaloacetate by citrate synthase drives this reaction forward to produce more oxaloacetate.[13]
Cataplerotic Processes
Citric acid intermediates can leave the cycle to participate in the biosynthesis of other compounds. Citrate can be directed toward fatty acids, succinyl-CoA to heme synthesis, alpha-ketoglutarate to amino acid synthesis, purine and neurotransmitter synthesis, oxaloacetate to amino acid synthesis, and malate to gluconeogenesis.[14][4]
Anaplerotic Processes
Intermediates are inserted into the TCA cycle to replace the cataplerotic processes and ensure the continuation of the cycle. For instance, pyruvate can enter the cycle throughout the body through pyruvate carboxylase, which inserts additional oxaloacetate into the cycle. This process causes the reaction to be pushed forward toward the already exergonic citrate synthase, as there is more oxaloacetate to participate in the reaction. The liver is another example, as it can produce alpha-ketoglutarate by oxidative deamination or transamination of glutamate.[15][4]
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