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The citric acid cycle is the central metabolic hub of the cell. It is the final common pathway for the oxidation of fuel molecule such as amino acids, fatty acids, and carbohydrates. 

It is the gateway to the aerobic metabolism of any molecule that can be transformed into an acetyl group or dicarboxylic acid. The cycle is also an important source of precursors, not only for the storage forms of fuels, but also for the building blocks of many other molecules such as amino acids, nucleotide bases, cholesterol, and porphyrin (the organic component of heme).

TCA cycle is vital since none of the enzyme deficiencies have so far been encountered perhaps the enzyme deficiencies are incompatible with life. Indirect evidence of its importance for life can be considered form the fact that the inhibitors of TCA cycle act as poisons.

An overview of TCA cycle

 The citric acid cycle (Krebs cycle, Tricarboxylic acid cycle) includes a series of oxidation-reduction reactions in mitochondria that result in the oxidation of an acetyl group to two molecules of carbon dioxide and reduce the coenzymes that are reoxidized through the electron transport chain, linked to the formation of ATP. 

Figure-1- Showing the reactions of TCA cycle

A four- carbon compound (oxaloacetate) condenses with a two-carbon acetyl unit to yield a six-carbon tricarboxylic acid (citrate). An isomer of citrate is then oxidatively decarboxylated. The resulting five-carbon compound (α-ketoglutarate) also is oxidatively decarboxylated to yield a four carbon compound (succinate).

Oxaloacetate is then regenerated from succinate. Two carbon atoms enter the cycle as an acetyl unit and two carbon atoms leave the cycle in the form of two molecules of carbon dioxide.

The four-carbon molecule, oxaloacetate that initiates the first step in the citric acid cycle is regenerated at the end of one passage through the cycle. The oxaloacetate acts catalytically: it participates in the oxidation of the acetyl group but is itself regenerated. Thus, one molecule of oxaloacetate is capable of participating in the oxidation of many acetyl molecules.

Significance of TCA cycle

Since TCA cycle functions in both oxidative and synthetic processes, it is amphibolic.

A) Catabolic role- The function of the citric acid cycle is the harvesting of high-energy electrons from carbon fuels. Glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of the cycle.

Energy yield per Acetyl co A per turn of cycle

As a result of oxidations catalyzed by the dehydrogenases of the citric acid cycle, three molecules of NADH and one of FADH2 are produced for each molecule of acetyl-CoA catabolized in one turn of the cycle. These reducing equivalents are transferred to the respiratory chain, where reoxidation of each NADH results in formation of 3, and 2 ATP of FADH2. Consequently, 11 high-transfer-potential phosphoryl groups are generated when the electron-transport chain oxidizes 3 molecules of NADH and 1 molecule of FADH2, In addition, 1 ATP (or GTP) is formed by substrate-level phosphorylation catalyzed by succinate thiokinase.

The net reaction of the citric acid cycle is-


Thus, 1 acetate unit generates approximately 12 molecules of ATP. In dramatic contrast, only 2 molecules of ATP are generated per molecule of glucose (which generates 2 molecules of acetyl CoA) by anaerobic glycolysis. 

Requirement of oxygen– Oxygen is required for the citric acid cycle indirectly in as much as it is the electron acceptor at the end of the electron-transport chain, necessary to regenerate NAD+ and FAD. The citric acid cycle, in conjunction with oxidative phosphorylation, provides the vast majority of energy used by aerobic cells in human beings, greater than 95%.


Figure-2- showing process of energy release from TCA cycle by oxidative phosphorylation

B) Anabolic role-As a major metabolic hub of the cell, the citric acid cycle also provides intermediates for biosynthesis of various compounds.

i) Role in Gluconeogenesis– All the intermediates of the cycle are potentially glucogenic, since they can give rise to oxaloacetate, and hence net production of glucose (in the liver and kidney, the organs that carry out gluconeogenesis. The key enzyme that catalyzes net transfer out of the cycle into gluconeogenesis is phosphoenolpyruvate carboxykinase, which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate, with GTP acting as the phosphate donor. 


Figure-3- showing the formation of Phosphoenolpyruvate from oxaloacetate, that can  also be  used for the synthesis of glycine, Serine and Cysteine besides forming glucose.

Net transfer into the cycle occurs as a result of several reactions. Among the most important of such Anaplerotic reactions is the formation of oxaloacetate by the carboxylation of pyruvate, catalyzed by pyruvate carboxylase. This reaction is important in maintaining an adequate concentration of oxaloacetate for the condensation reaction with acetyl-CoA. If acetyl-CoA accumulates, it acts as both an allosteric activator of pyruvate carboxylase and an inhibitor of pyruvate dehydrogenase, thereby ensuring a supply of oxaloacetate.

Lactate, an important substrate for gluconeogenesis, enters the cycle via oxidation to pyruvate and then carboxylation to oxaloacetate.

Aminotransferase (transaminase) reactions form pyruvate from alanine, oxaloacetate from aspartate, and Alpha-keto glutarate from glutamate. Other amino acids contribute to gluconeogenesis because their carbon skeletons give rise to citric acid cycle intermediates. Alanine, cysteine, glycine, hydroxyproline, serine, threonine, and tryptophan yield pyruvate; arginine, histidine, glutamine, and proline yield α-keto glutarate; isoleucine, methionine, and valine yield succinyl-CoA; tyrosine and phenylalanine yield fumarate.

The conversion of propionate to succinyl-CoA via the Methylmalonyl-CoA pathway is also important for gluconeogenesis.

ii) Role in synthesis of non essential amino acids Since the transamination reactions are reversible, the cycle also serves as a source of carbon skeletons for the synthesis of some amino acids like Alanine, aspartate, Asparagine Glutamate , glutamine etc. (Figure)


Figure-4- showing the formation of non essential amino acids from the TCA cycle intermediates. Glutamine can also be utilized for the synthesis of purine nucleotides

Glutamate- produced from Transamination reaction, upon decarboxylation produces GABA(Gamma amino butyric acid), that acts as a neurotransmitter.



Figure-5- showing the formation of non essential amino acids from TCA cycle intermediates. Aspartic acid can also be  utilized for the synthesis of pyrimidine  nucleotides

iii) Role in fatty acid synthesis Acetyl-CoA, formed from pyruvate by the action of pyruvate dehydrogenase, is the major substrate for long-chain fatty acid synthesis . Pyruvate dehydrogenase is a mitochondrial enzyme, and fatty-acid synthesis is a cytosolic pathway; the mitochondrial membrane is impermeable to acetyl-CoA. Acetyl-CoA is made available in the cytosol from citrate synthesized in the mitochondrion, transported into the cytosol, and cleaved in a reaction catalyzed by ATP-citrate lyase. Acetyl co A can also be used for the synthesis of Acetyl choline, cholesterol, steroids, ketone bodies, and is also required for detoxification reactions etc.



Figure-6- showing transportation of citrate out of mitochondrion to provide Acetyl co A for fatty acid or cholesterol synthesis

Citrate is only available for transport out of the mitochondrion when Aconitase is saturated with its substrate, and citrate cannot be channeled directly from citrate synthase onto Aconitase. This ensures that citrate is used for fatty acid synthesis only when there is an adequate amount to ensure continued activity of the cycle.

Citrate, besides transporting Acetyl co A, the precursor for fatty acid, outside the mitochondria,  also acts as a positive modifier for Acetyl co A carboxylase enzyme and thus promotes de novo fatty acid synthesis.

Citrate regulates rate of glycolysis also, it acts as a negative modifier for PFK-1 enzyme and thus inhibits Glycolysis,

iv) Role in Haem synthesis Succinyl co A condenses with amino acid Glycine to form Alpha amino beta keto adipic acid, which is the first step of haem biosynthesis.

Succinyl co A is required for the utilization of ketone bodies. It also acts as neuro transmitter.

v) Role in purine and pyrimidine synthesis Glutamate and Aspartate derived from TCA cycle are utilized for the synthesis of purines and pyrimidine.



Figure-7- showing the bio synthetic role of TCA cycle

Thus, the intermediates of TCA cycle are utilized in both ways , they are oxidized to yield energy or are utilized for bio synthetic reactions depending upon the need of the body.


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