Introduction to the TCA Cycle:
The Tricarboxylic Acid (TCA) cycle is a crucial metabolic pathway responsible for supplying energy to the body, accounting for approximately 70% of total ATP production. Within this sequence of processes, energy is produced in a number of steps.
Most of the energy obtained from the TCA cycle is captured by NAD+ and FAD and converted later to ATP via the electron transport chain, the third stage of cellular respiration through the process of oxidative phosphorylation. For each turn of the TCA cycle, three NAD⁺ molecules are reduced to NADH + H⁺, and one FAD molecule is converted into FADH₂.
In eukaryotic cells, mitochondria house the enzymes responsible for respiration and energy production. In bacteria, these enzymes are embedded within the plasma membrane. Because glucose, fatty acids, and many amino acids are all broken down into acetyl-CoA, the citric acid cycle (TCA cycle) serves as a central metabolic pathway, representing the final common route for the oxidation of carbohydrates, fats, and proteins.
Therefore, it is the process that makes a large portion of the free energy released by the oxidation of lipids, carbohydrates, and amino acids available.
The amphibolic nature of the TCA cycle makes it even more significant because it produces precursor compounds for the production of other biomolecules, such as glucose, fatty acids, and amino acids. Each cycle generates two carbon dioxide molecules, three NADH molecules, three protons (H⁺), one FADH₂ molecule, and one GTP molecule. Every glucose molecule results in the production of two pyruvate molecules, which in turn yield two acetyl-coA molecules.
Consequently, this is doubled for every glucose molecule. The citric acid cycle is called an amphibolic pathway since it is a part of both catabolic and anabolic processes. The TCA cycle’s intermediates serve as building blocks for both anabolic and catabolic functions.
Anabolic Functions of the TCA Cycle:
Biosynthesis uses the intermediates of the citric acid cycle as substrates. Important chemicals that will have major cataplerotic impacts on the cycle are synthesized using a number of the intermediates of the citric acid cycle.
Acetyl-CoA cannot directly cross the mitochondrial membrane, so instead, citrate is exported from the citric acid cycle and transported into the cytosol through the inner mitochondrial membrane. This typically occurs in a well-fed state, where high levels of NADH + H⁺ inhibit the dehydrogenase enzymes that act after citrate formation, leading to citrate accumulation. The excess citrate is then shuttled out of the mitochondrial matrix. In the cytosol, ATP citrate lyase converts citrate into acetyl-CoA and oxaloacetate. The oxaloacetate is subsequently returned to the mitochondria. The cytosolic acetyl-CoA is then used for the synthesis of fatty acids and cholesterol. Cholesterol, in turn, serves as a precursor for vitamin D, bile salts, and steroid hormones. Additionally, intermediates of the citric acid cycle are utilized to form the carbon backbones of many non-essential amino acids.
The α-keto-acids that are produced from the intermediates of the citric acid cycle must undergo a transamination reaction with glutamate in order to obtain their amino groups.
Oxaloacetate, which creates aspartate and asparagine, α ketoglutarate, which forms glutamine, proline, and arginine, and GABA, a neurotransmitter, are the intermediates that can supply the carbon skeletons for amino acid synthesis.
Aspartate and glutamine are crucial amino acids involved in the formation of purines, the nitrogenous bases found in DNA and RNA, as well as in essential biomolecules such as ATP, AMP, GTP, NAD, FAD, and CoA. Furthermore, succinyl-CoA, an intermediate of the citric acid cycle, provides the majority of the carbon atoms required for porphyrin synthesis. These molecules are a crucial part of the heme proteins, which include different cytochromes, hemoglobin, and myoglobin.
Gluconeogenesis involves the reduction of mitochondrial oxaloacetate to malate, which is subsequently carried out of the mitochondrion and oxidized back to oxaloacetate in the cytosol. Almost all gluconeogenic precursors, including lactate and glucogenic amino acids, are converted into glucose by the liver and kidney at a rate that is limited by the decarboxylation of cytosolic oxaloacetate to phosphoenolpyruvate-by-phosphoenolpyruvate carboxykinase.
Malate formed during TCA cycle can be converted to pyruvate using Malic acid which can again be converted to phosphoenol pyruvate throughoxaloacetate by pyruvate carboxylase and phosphoenolpyruvate carboxykinase to get gluconeogenesis going.
Catabolic Functions of the TCA Cycle:
- In TCA cycle, three NADH + H+ are released in the oxidative decarboxylation of isocitarte to oxalosuccinate, α-ketoglutarate to succinyl CoA, and malate to oxaloacetate.
- Two molecules are released during the oxidative decarboxylation of oxalosuccinate to α ketoglutarate and α-ketoglutarate to succinyl CoA.
- A molecule of FADH₂ is formed when succinate is converted into fumarate.
- Most of the energy obtained from the TCA cycle is captured by NAD+ and FAD and converted later to ATP via the electron transport chain, the third stage of cellular respiration through the process of oxidative phosphorylation.
- The conversion of succinyl CoA to succinate involves substrate-level phosphorylation of GDP to GTP.
One significant cycle in plants is the glyoxylate cycle, which is a variation of TCA. Acetate can serve as the sole carbon source for all carbon molecules produced by plants, particularly seedlings. When acetyl CoA reaches the TCA cycle, it is fully oxidized to produce two CO2 molecules. Therefore, unless alternate reactions are possible, the cycle cannot provide the vast numbers of biosynthetic precursors required for acetate-based growth.
By avoiding the TCA cycle’s decarboxylations, bacteria and plants use a variant of the TCA cycle known as the glyoxylate cycle to create four carbon dicarboxylic acids from acetyl CoA. Where photosynthesis is not feasible, the glyoxylate cycle is crucial for seed germination. Acetyl CoA is produced by the breakdown of triacylglycerols found in oilseeds. Acetyl CoA is converted to oxaloacetate by glyoxysomes that form during germination, and this oxaloacetate is then used for gluconeogenesis, which turns it into glucose. The glyoxysomes vanish as soon as the developing seedling starts using photosynthesis to make carbohydrate.
The enzyme nucleoside diphosphate kinase converts GTP to ATP.
Anaplerotic Processes in the TCA Cycle:
To ensure that the citric acid cycle continues, intermediates can be added to replace cataplerotic processes. For instance, pyruvate carboxylase allows pyruvate to join the cycle throughout the body, adding more oxaloacetate to the cycle. The cycle is accelerated by this rise in oxaloacetate. Oxaloacetate + ADP + Pi = Pyruvate + CO2 + ATP
Additionally, succinyl CoA can be restored using propionyl CoA. The production of bile acids, the breakdown of amino acids such as valine, isoleucine, threonine, and methionine, and the oxidation of odd and branched chain fatty acids are the sources of propionyl CoA.