Regulation of the Citric Acid Cycle by NADH

Regulation of the Citric Acid Cycle by NADH

The Citric Acid Cycle is regulated mainly by the availability of substrates and by feedback inhibition by its products ( One such example of product inhibition is the regulation of the cycle by the reduced form of nicotinamide adenine dinucleotide (NADH), three molecules of which are formed in one turn of the cycle.

NADH –specifically, a high [NADH] / [NAD+] ratio – also inhibits pyruvate dehydrogenase, which is the enzyme that converts pyruvate to the acetyl-CoA that enters the cycle in its first step. This ratio increases in conditions of fatty acid oxidation, for example, during starvation. The increase in the [NADH] / [NAD+] ratio inhibits the pyruvate dehydrogenase complex, which will then effect into a sparing of carbohydrates. In conditions such as starvation, this sparing of carbohydrates makes sense.

Moreover, NADH inhibits the enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, which catalyze two of the reactions in which NADH is formed. Along with ATP, which also inhibits the two enzymes, levels of NADH increase when the cell has abundant energy stores. Increased NADH levels, therefore, serve to signal the cell that it does not need to produce as much energy through the citric acid cycle (Champe, Harvey, & Ferrier, 2005).

Regulation of Fatty Acid Catabolism

The catabolism of fatty acids is regulated by several factors, depending mostly on the nutritional status of the individual. This is because fatty acids serve as the body’s major fuel storage reserve (Champe, Harvey, & Ferrier, 2005).

In starvation states, the low insulin/glucagon ratio favors degradation of fatty acids, usually in the muscle and in the liver. Once the fatty acids are fully oxidized, they yield acetyl-CoA, which are then further processed by the citric acid cycle to yield the energy especially needed by the body during timesof starvation.

On the other hand, after a carbohydrate-rich meal, the insulin/glucagon ratio increases. This stimulates fatty acid synthesis, as a way of storing excess energy. When fatty acid synthesis is occurring in the cytosol of the cell, levels of malonyl CoA increase, and this compound inhibits the carnitine shuttle that transports long-chain fatty acids into the mitochondria. Without the carnitine shuttle, fatty acid oxidation cannot proceed and is therefore inhibited (Champe, Harvey, & Ferrier, 2005). This is only logical, since the body still has enough energy derived from the carbohydrate-rich meal and does not need the acetyl-CoA that would otherwise have been formed from fatty acid catabolism.

Regulation of the Urea Cycle

Urea is the form in which amino groups that are derived from amino acids are disposed.

When an individual ingests a protein-rich meal, levels of glutamate and arginine increase. Glutamate is added to acetyl-CoA to form N-acetylglutamate, in a reaction that is activated by arginine. In other words, a meal rich in proteins results in increased levels of N-acetylglutamate. N-acetylglutamate, for its part, is an essential activator for carbamoyl phosphate synthetase I, which is the enzyme that governs the rate-limiting step in the urea cycle. It therefore increases the production of urea. In short, a meal rich in proteins – of which amino acids are the building blocks – stimulates, through N-acetylglutamate, the production of urea. This is necessary since urea is the form in which these amino acids are disposed by the body. Thus, this helps maintain the nitrogen balance in the body.


Champe, P. C., Harvey, R. A., & Ferrier, D. R. (2005). Lippincott’s Illustrated Reviews: Biochemistry. Philadelphia: Lippincott Wiliams & Wilkins.

Citric Acid Cycle. (2008). In Wikipedia, the free encyclopedia. Retrieved October 7, 2008, from Wikipedia:

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