Cahill cycle


The Cahill cycle, also known as the alanine cycle or glucose-alanine cycle, is the series of reactions in which amino groups and carbons from muscle are transported to the liver. It is quite similar to the Cori cycle in the cycling of nutrients between skeletal muscle and the liver. When muscles degrade amino acids for energy needs, the resulting nitrogen is transaminated to pyruvate to form alanine. This is performed by the enzyme alanine transaminase, which converts L-glutamate and pyruvate into α-ketoglutarate and L-alanine. The resulting L-alanine is shuttled to the liver where the nitrogen enters the urea cycle and the pyruvate is used to make glucose.
The Cahill cycle is less productive than the Cori cycle, which uses lactate, since a byproduct of energy production from alanine is production of urea. Removal of the urea is energy-dependent, requiring four "high-energy" phosphate bonds, thus the net ATP produced is less than that found in the Cori cycle. However, unlike in the Cori cycle, NADH is conserved because lactate is not formed. This allows for it to be oxidized via the electron transport chain.
The alanine cycle also serves other purposes:
This cycle is an important part of mammal physiology, but its presence and physiological significance in non-mammalian land vertebrates is unclear. For example although some fish use alanine as a nitrogen carrier, the cycle is unlikely to take place due to a slower glucose turnover rate and lower release of alanine from exercising muscle tissue.
The Cahill cycle ultimately serves as a method of ridding the muscle tissue of the toxic ammonium ion, as well as indirectly providing glucose to energy-deprived muscle tissue. Under long periods of fasting, skeletal muscle can be degraded for use as an energy source to supplement the glucose being produced from the breakdown of glycogen. The breakdown of branch chain amino acids yields a carbon skeleton utilized for energy purposes, as well as free ammonium ions, the levels of which can quickly accumulate. Because skeletal muscle is unable to utilize the urea cycle to safely dispose of the ammonium ion, it must get rid of it in a different way. To do so, the ammonium is combined with free α-ketoglutarate via a transamination reaction in the cell, yielding glutamate and α-keto acid. Alanine aminotransaminase then coverts glutamate back into α-ketoglutarate, this time transferring the ammonium to pyruvate resulting from glycolysis, forming free alanine. The alanine amino acid acts as a shuttle - it leaves the cell, entering the blood stream and traveling to hepatocytes in the liver, where essentially this entire process is reversed. Alanine undergoes a transamination reaction with free α-ketoglutarate to yield glutamate, which is then deaminated to form pyruvate and, ultimately, free ammonium ion. Hepatocytes are capable of metabolizing the toxic ammonium by the urea cycle, thus disposing of it safely. Having rid the muscle cells of the ammonium ion successfully, the cycle then provides the energy-deprived skeletal muscle cells with glucose. Pyruvate formed from the deamination of glutamate in the hepatocytes undergoes gluconeogenesis to form glucose, which can then enter the bloodstream and be shuttled to the skeletal muscle tissue, thus providing it with the energy source it needs.