TCA Cycle as an Amphibolic Pathway, It's Function and Regulation

Tricarboxylic Acid Cycle: An Amphibolic Pathway

The word amphi refers to the property of dual character with opposite nature. Here in case of TCA cycle, amphibolic means property of this cycle having both catabolic as well as anabolic processes. As there is the continuous and cyclic fluctuation of compounds with four, five and six carbons in this cycle we can easily regard it as the amphibolic pathway.

TCA Cycle as Anabolic pathway:

TCA cycle, being the universal metabolic hub of most of the organisms have the ability to produce precursors for many biosynthetic pathways. For example: in the case of lack of glucose in the cells oxaloacetate, an outcome of TCA cycle undergoes gluconeogenesis thus fulfilling the glucose demand of the cell. Here are some significantly important precursors produced by the TCA cycle that are utilized for the synthetic purposes:

• Succinyl CoA, another product of TCA cycle, is utilized for the anabolic synthesis of porphyrin ring of hemoglobin and myoglobin that help as an oxygen carrier in the body of higher animals. And as electron carriers in cytochromes.
• Oxaloacetate undergoes gluconeogenesis reaction to produce glucose molecules in the cells. During starvation in the body there is the lack of external supply of glucose. At such unfavorable condition, oxaloacetate undergoes an anabolic reaction called gluconeogenesis to fulfill the required glucose supply to the body.
• α-ketoglutarate and oxaloacetate can be utilized to synthesize amino acids and with a simple transmission reaction, can be converted into glutamate and aspartate respectively. These molecules are further rearranged to give actual amino acids as well as nucleotides (purine and pyrimidine)
• Citric acid or simply citrate is another important product of TCA cycle. Citric acid can play a vital role as a precursor in the synthesis of fatty acids and isoprenoids synthesis. Citrate is a commercially important product that is produced utilizing microorganisms and is used in wide r5ange of purposes.

Furthermore, we can see a reaction in TCA cycle itself as an anabolic pathway. Formation of 6 carbon molecule citrate by the combination of a 2 carbon molecule acetyl-CoA and a 4 carbon molecule oxaloacetate is visually an anabolic construction reaction.

TCA Cycle as Catabolic Pathway:

TCA cycle as many times said is a universal pathway for oxidative catabolism of carbohydrates, proteins, fatty acids and the likes. In TCA cycle series of catabolic reactions like step 3, and step 5 are high energy yielding steps. Mostly catabolic steps of TCA are exergonic in nature and are significantly important as energy harvesting steps.

Anaplerotic Reactions (Replenish Citric Acid Cycle Intermediates)

In TCA cycle four and five-carbon molecules are highly affiants towards forming the macromolecules, self-being precursors. In this course, they tend to discontinue the cycle and finally leave the cyclic path and follow the synthetic pathway. However, the TCA cycle is run continuously. Curiously one can raise a question "how?".

Well, when the intermediates leave the cycle, then the roles of those intermediates are replaced or fulfilled by other replenishing reactions called anaplerotic reactions. There is no net change in the concentration of the intermediates in the citric acid cycle because the intermediates leaving the cycle and reactions which replenish them are in dynamic balance.

Anaplerotic Reactions may vary from organism to organism and cell to cell. Here are some examples of anaplerotic Reactions with corresponding organisms/ organs/ tissues:

Energy generation in TCA Cycle

TCA cycle as talked many times is a superlative pathway in case of energy production within a cell. More than 70% of total energy in overall metabolic hub is the outcome of TCA cycle. Not all steps involved in this cycle are exergonic but none of the reactions are endergonic i.e. gross ATP production = Net ATP production. Following is the energy profile of TCA cycle per cycle:

During the gateway reaction, there is also the production of 1 NADH + H⁺ during the formation of acetyl-CoA. Somewhere we can find that this is also counted in an energy profile of TCA which makes a total of 15 ATPs from 1 complete TCA cycle.

Functions of TCA Cycle:

• TCA cycle provides energy to cells:

The primary function of TCA cycle in prokaryotes and eukaryotes is to act as the main source of energy. From each complete turn of TCA cycle, 12 molecules of ATPs are produced which is equivalent to 2/3 of total ATPs produced in overall metabolism.

• TCA cycle provides intermediates for other pathways:

Generally, four and five-carbon molecules of TCA cycle get withdrawn from the cycle for the synthesis of other cellular ingredients such as carbohydrate, protein, fatty acids etc. For example, oxaloacetate undergoes gluconeogenesis to synthesize glucose.

Enzymes of TCA cycle are utilized in fatty acid synthesis.

• TCA cycle enzymes also participate in shuttling (carrying) the reducing equivalents inside the mitochondrial matrix.

Regulation of TCA

• Conversion of pyruvate to acetyl-CoA:

During the regulation of TCA cycle, there is inhibition of pyruvate dehydrogenase complex by the high concentration of ATP, acetyl-CoA, and NADH. The presence of these molecules signifies that there is sufficient amount or energy source in the cell and there is no need to further synthesize the ATPs in the cell.

• Synthesis of citric acid from oxaloacetate and acetyl-CoA:

The high concentration of ATP inhibits the enzyme, citrate synthetase. This is also due to the same logical reason.

• Oxidation and decarboxylation of isocitrate to α-keto glutarate:

The enzyme involved here, Isocitrate dehydrogenase is inhibited by the high concentration of ATP and NADH in the cells.

• Inhibition of succinate dehydrogenase:

The high concentration of malonate (normally is not present in a cell) blocks the activity of citric acid. This activity can be reversed by the high concentration of calcium ions.