ALPHA-KETOGLUTARATE: PROPERTIES, FUNCTIONS AND APPLICATIONS - CHEMISTRY - 2025

The alpha - ketoglutarate is an organic salt produced from the dissociation of the acid-ketoglutaric. It is a compound that has medical use, and that is also present in eukaryotic and prokaryotic cells, forming part of the Krebs cycle (of citric acid or tricarboxylic acids).

This cycle is of great biological importance, since it acts as an intermediary between glycolysis and the electronic transport chain, which in turn is associated with oxidative phosphorylation, a process responsible for the metabolic production of ATP.

Structural formula of alpha-ketoglutarate anion. Its two negative charges must be balanced by the presence of cations, giving rise to a salt. Source: NEUROtiker / Public domain

Alpha-ketoglutarate is administered intravenously, in order to prevent heart injuries during cardiac surgeries, related to blood flow problems. It is also used to prevent muscle deterioration, as a result of surgery or trauma.

It is used in the manufacture of drugs for kidney diseases, intestinal and stomach disorders, as well as for many conditions; however, the scientific evidence for these uses is weak and scant.

This salt fulfills many functions, including the generation of amino acids, such as proline, glutamine and glutamic acid. It also intervenes in immunological processes, and in the improvement of the structure and functioning of the bone system.

Properties

Appearance

White powder or crystalline yellow powder.

Synonyms

α-ketoglutarate, 2-oxoglutarate, and 2-ketoglutarate.

IUPAC preferred name: 2-oxo-pentanedioate.

Molar mass

144.08 g / mol

Molecular formula

C ₅ H ₄ O ₅ ^2-

Note that it is an anion, which has to be accompanied by a cation to balance its negative charge; be it Na ⁺, K ⁺, Ca ²⁺ or others.

Water solubility

56.5 g / L

Melting point

113 - 115 ºC

Boiling point

It decomposes before boiling.

Features

Krebs cycle

Alpha-ketoglutarate is a compound that is part of the Krebs cycle. It is formed from the action of the enzyme isocitrate dehydrogenase on the isocitrate with the generation of NADH and CO ₂. Furthermore, alpha-ketoglutarate is a site of incorporation into the Krebs cycle of glutamic acid, an amino acid.

Glutamic acid is transformed into alpha-ketoglutarate, this being a way to avoid the depletion of the components of the Krebs cycle. The pathways that fulfill this function are called anaplerotic. Subsequently, the alpha-ketoglutarate is converted to succinyl CoA.

Alpha-ketoglutarate is a determining factor in the speed of the Krebs cycle and is involved in several metabolic pathways. It is also a source of energy for cell function, just as it happens with intestinal cells.

Synthesis of amino acids

Alpha-ketoglutarate is involved directly or indirectly in the formation of various amino acids. When present in the diet, it is converted in intestinal cells (enterocytes) to proline and leucine, among other amino acids.

Alpha-ketoglutarate is a source for the synthesis of glutamine and glutamic acid (glutamate); amino acids that stimulate protein synthesis. Glutamate, a neutral transmitter, released from nerve endings in bone tissue, and in the process of incorporating amine into alpha-ketoglutarate, produces proline.

Proline is a vital amino acid for the synthesis of collagen: a fibrous protein that is very abundant in mammals and is part of the skin, bones, tendons, cartilage and teeth.

On the other hand, alpha-ketoglutarate directs the transformation of proline into hydroxyproline. This causes the transformation of procollagen into collagen, and the formation of the bone matrix.

Alpha-ketoglutarate activates prolidase, an enzyme that is involved in the recycling of proline. In addition, it influences bone tissue through the action of glutamate and glutamine.

These amino acids activate the synthesis of the amino acids ornithine and arginine, which stimulate the secretion of growth hormone.

Nitrogen transport

Alpha-ketoglutarate is involved in the process of transporting and eliminating nitrogen produced by cells. The amino groups present in amino acids are transferred to alpha-ketoglutarate by a transamination process. These amino groups are then transferred to the liver.

In the liver, the urea cycle occurs. The latter and ammonium (NH ₄ ⁺) are the main forms of nitrogen excretion in urine. Additionally, alpha-ketoglutarate plays an important role in brain nitrogen detoxification.

Longevity and aging

Alpha-ketoglutarate would act by increasing the life expectancy in the Caenorhabditis elegans worm, acting specifically on the TOR (target of rapamycin) complex. This complex has been related to diseases that increase their incidence during the old age phase of humans.

One form of TOR, TORC1, is implicated in the onset of diabetes, heart disease and cancer in old age. TORC1 has been identified as the relationship between cellular senescence and the generation of these diseases.

Alpha-ketoglutarate appears to play a role in the inhibition of the TOR complex, therefore it would play an important role in increasing life expectancy in humans. Inhibition of TORC1 in elderly humans reduces the incidence of infections.

Antioxidant function

Alpha-ketoglutarate acts as an antioxidant agent, being able to react with hydrogen peroxide to form succinate, water, and carbon dioxide. In addition, it is capable of reacting with other components of reactive oxygen species (ROS).

Relieves oxidative stress, acting as an energy source and antioxidant in mammalian cells. It also increases the antioxidant capacity by promoting the synthesis of glutamine.

Applications

In animals

Alpha-ketoglutarate is supplied to turkeys, pigs and rats, resulting in an improvement in bone quality, which could be caused by the positive effects of increased glutamate production, since it is involved in the regulation of bone metabolism.

Likewise, collagen synthesis increases, as a result of a greater supply of proline. Animals treated with alpha-ketoglutarate show increased weight, length, bone density, bone mineral content, and elastic bone strength.

In humans

Alpha-ketoglutarate is thought to help increase muscle protein synthesis in postoperative patients, as well as improve amino acid metabolism in dialysis patients.

Doctors give it intravenously to patients during heart surgery to prevent heart injury, and also to prevent muscle breakdown after surgery. The compound helps in the production of muscle tissue and heal wounds.

Alpha-ketoglutarate has been used for different purposes and conditions in humans, such as to help fight bacterial infections, liver problems, cataracts, and to improve protein processing by dialysis patients. It also helps improve athletic performance.

References

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2. Wu, N., Yang, M., Gaur, U., Xu, H., Yao, Y., & Li, D. (2016). Alpha-Ketoglutarate: Physiological Functions and Applications. Biomolecules & therapeutics, 24 (1), 1–8. doi.org/10.4062/biomolther.2015.078
3. National Center for Biotechnology Information. (2020). Alpha-Ketoglutarate. PubChem Database., CID = 164533. Recovered from: pubchem.ncbi.nlm.nih.gov
4. WebMD LLC. (2019). Alpha-ketoglutarate (AKG). Recovered from: webmd.com
5. Shaojuan Liu et al. (2018). The Antioxidative Function of Alpha-Ketoglutarate and Its Applications. doi.org/10.1155/2018/3408467
6. Barbara Beer et al. (2017). In vitro metabolic engineering for the production of α-ketoglutarate. doi.org/10.1016/j.ymben.2017.02.011
7. Royal Society of Chemistry. (2020). α-Ketoglutaric acid. Recovered from: chemspider.com