α-Ketoglutaric acid
α-Ketoglutaric acid (also termed 2-oxoglutaric acid) is a dicarboxylic acid, i.e., a short-chain fatty acid containing two carboxyl groups (carboxy groups notated as CO2H) with C, O, and H standing for carbon, oxygen, and hydrogen, respectively (see adjacent figure). However, almost all animal tissues and extracellular fluids have a pH above 7. At these basic pH levels α-ketoglutaric acid exists almost exclusively as its conjugate base. That is, it has two negative electric charges due to its release of positively charged hydrogen (i.e., H+) from both of its now negatively charged carboxy groups, CO−2 (see Conjugate acid-base theory). This double negatively charge molecule is referred to as α-ketoglutarate or 2-oxoglutarate.[2]
β-Ketoglutaric acid (also termed 3-oxoglutaric acid and acetonedicarboxlic acid) and its conjugate base, β-Ketoglutarate, differ from α-ketoglutaric acid and α-ketoglutarate by the position of their ketone, i.e., carbon–oxygen double bond (C=O). β-Ketoglutaric acid's and β-ketoglutarate's C=O is on the second carbon from a CO2H whereas α-ketoglutaric acid's and α-ketoglutarate's C=O is on a carbon adjacent to a CO2H. "Ketoglutaric acid" and "ketoglutarate", when not qualified as α or β, almost always refers respectively to α-ketoglutaric acid or α-ketoglutarate.[2] β-Ketoglutarate does not have the biological actions that α-ketoglutarate has; it is even suggested to inhibit at least one action of α-ketoglutarate (see the following section titled, "β-Ketoglutaric acid and TET-2").[3] β-Ketoglutaric acid is used to synthesize other compounds (see applications of β-ketoglutaric acid) such as cyclohexenone which is itself widely used to synthesize other compounds.[4]
α-Ketoglutarate is an intermediate in the citric acid cycle; this cycle supplies the energy used by cells.[2] It is also an intermediate in or product of several other metabolic pathways.[2][5] These include its being a component of metabolic pathways that: make key amino acids and in the process regulate the cellular levels of carbon, nitrogen, and ammonia;[5] reduce the cellular levels of potentially toxic reactive oxygen species;[6][7] and synthesize the neurotransmitter gamma-aminobutyric acid.[8] It also acts as a direct stimulator of, or cofactor (i.e., required for but does not itself stimulate) for various cellular functions as defined in studies that are primarily preclinical (i.e., conducted in animal models of disease or on animal or human tissues). These studies have provided evidence that α-ketoglutarate contributes to regulating: kidney function;[9] the benefits that resistance exercise has in reducing obesity, strengthening muscles, and preventing muscle atrophy;[10] glucose tolerance as defined in glucose tolerance tests;[11] aging and the development of changes that are associated with aging including old age-related disorders and diseases;[12] the development and/or progression of certain types of cancer and inflammations;[13] and the differentiation of immature T cells into mature T cells.[14]