2-Ketoglutaric acid targets 2-oxoglutarate-dependent dioxygenases (serves as a co-substrate) [1]
2-Ketoglutaric acid targets tyrosinase (Ki = 1.86 mM) [2]

In addition to its physiological roles, 2-ketoglutarate (also known as alpha-ketoglutarate) also protects against lipid peroxidation, reduces ammonia levels produced in the lungs, and provides neuroprotection against cyanide poisoning [1]. The synthesis of nucleotides and amino acids requires 2-oxoglutarate as a precursor [2].

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- As a co-substrate, 2-Ketoglutaric acid activates 2-oxoglutarate-dependent dioxygenases, which are involved in diverse biological processes including collagen biosynthesis, histone/DNA demethylation, and proline hydroxylation [1]
- 2-Ketoglutaric acid exhibited dose-dependent inhibitory activity against tyrosinase; at 5 mM, it inhibited tyrosinase activity by 68%, and the inhibition followed a non-competitive kinetic mechanism [2]
- Molecular dynamics simulation showed that 2-Ketoglutaric acid bound to the active site of tyrosinase, inducing conformational changes in the enzyme’s catalytic pocket and reducing its affinity for the natural substrate L-tyrosine [2]
- The inhibitory effect of 2-Ketoglutaric acid on tyrosinase was reversible, with enzyme activity recovering by 85% after dialysis to remove the compound [2]

- 2-Oxoglutarate-dependent dioxygenase activity assay: The reaction system contained recombinant 2-oxoglutarate-dependent dioxygenase, substrate (e.g., proline-containing peptide, methylated histone), 2-Ketoglutaric acid (0.1-5 mM), Fe²⁺, and ascorbate; the reaction was incubated at 37°C for 30-60 minutes, and the product (e.g., hydroxylated peptide, demethylated histone) was detected by chromatographic or mass spectrometric methods to evaluate enzyme activity [1]
- Tyrosinase activity assay: The assay was performed in a buffer system with L-dopa as the substrate; serial concentrations of 2-Ketoglutaric acid (0.1-10 mM) were added to the mixture of tyrosinase and L-dopa, and the oxidation of L-dopa to dopachrome was monitored spectrophotometrically at 475 nm for 10 minutes; kinetic parameters (Km, Vmax, Ki) were calculated by nonlinear regression analysis [2]
- Tyrosinase conformational analysis: Molecular dynamics simulation was conducted using tyrosinase crystal structure; 2-Ketoglutaric acid was docked into the enzyme’s active site, and the complex was subjected to simulation for 100 ns to analyze changes in protein backbone flexibility, hydrogen bonding, and active pocket volume [2]

[1]. Huergo LF, et al. The Emergence of 2-Oxoglutarate as a Master Regulator Metabolite. Microbiol Mol Biol Rev. 2015 Dec;79(4):419-35.
[2]. Gou L, et al. The effect of alpha-ketoglutaric acid on tyrosinase activity and conformation: Kinetics and molecular dynamics simulation study. Int J Biol Macromol. 2017 Dec;105(Pt 3):1654-1662.

2-Ketoglutarate is an oxodicarboxylic acid, formed by introducing an oxosubstituent at the 2-position of glutarate. It is an intermediate metabolite in the Krebs cycle and an important metabolite. Functionally, it is related to glutarate and is the conjugate acid of 2-ketoglutarate (1-). α-Ketoglutarate (α-ketoglutarate) is not currently approved for any indication, but it is an investigational drug in the United States. In the US, a Phase I clinical trial is investigating whether α-ketoglutarate precursors in nutritional supplements can benefit patients with propionic acidemia. α-Ketoglutarate is sold as a dietary supplement to athletes to improve athletic performance by helping to remove excess ammonia from the body, but it has not been formally approved for this indication. Currently, only experimental studies have shown that α-ketoglutarate can lower ammonia levels in hemodialysis patients. Physiologically, α-ketoglutarate acts as an intermediate in the tricarboxylic acid cycle, participating in transamination reactions in amino acid metabolism, combining with ammonia to form glutamate, and can combine with nitrogen to reduce nitrogen. Multiple experimental studies have shown that α-ketoglutarate supplementation helps alleviate the common postoperative reduction in muscle protein synthesis. α-Ketoglutarate is a metabolite found in or produced by Escherichia coli (K12, MG1655 strains). 2-Ketoglutarate has been found in hops, fruit flies, and other organisms with relevant data. It is a class of carbonyl compounds with the general formula 1,5-glutaric acid. (Excerpt from Lehninger, Principles of Biochemistry, 1982, p. 442)

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Drug Indications
α-Ketoglutarate is not currently approved for any indication, but it is an investigational drug in the United States. Potential indications for α-ketoglutarate include patients with propionic acidemia and trauma patients with muscle atrophy.

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Mechanism of Action
The exact mechanism of action of α-ketoglutarate has not been elucidated. Some of the functions of α-ketoglutarate include: participating in the tricarboxylic acid cycle as an intermediate; participating in transamination reactions in amino acid metabolism; combining with ammonia to form glutamate; and combining with nitrogen to reduce nitrogen. Regarding the role of α-ketoglutarate in relation to ammonia, some studies have suggested that α-ketoglutarate can help improve the condition of patients with propionic acidemia who have high blood ammonia levels and low glutamine/glutamate levels. Since endogenous glutamate/glutamine is converted from α-ketoglutarate, and the production of α-ketoglutarate is impaired in patients with propionic acidemia, supplementation with α-ketoglutarate should improve the condition of these patients. Other experimental studies have also shown that adding α-ketoglutarate to the parenteral nutrition of postoperative patients helps alleviate the common postoperative reduction in muscle protein synthesis. This reduction in muscle synthesis is thought to be caused by low α-ketoglutarate levels.
Pharmacodynamics
All the physiological functions of α-ketoglutarate have not been fully elucidated. It is known that α-ketoglutarate participates in the Krebs cycle, transamination reactions, and promotes muscle synthesis.

C5H6O5

146.09814

146.021

328-50-7

2-Ketoglutaric acid Sodium;22202-68-2;2-Ketoglutaric acid-13C5;161096-83-9;2-Ketoglutaric acid-13C;108395-15-9;Calcium 2-oxoglutarate;71686-01-6;2-Ketoglutaric acid-d4;1381759-60-9;2-Ketoglutaric acid-d6;1173021-86-7

51

Off-white to light yellow solid powder

1.5±0.1 g/cm3

345.6±25.0 °C at 760 mmHg

113-115 °C

177.0±19.7 °C

0.0±1.6 mmHg at 25°C

1.494

-1.43

2

5

4

10

171

0

OC(=O)CCC(=O)C(O)=O

KPGXRSRHYNQIFN-UHFFFAOYSA-N

InChI=1S/C5H6O5/c6-3(5(9)10)1-2-4(7)8/h1-2H2,(H,7,8)(H,9,10)

2-oxopentanedioic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~1711.16 mM)
H2O : ~50 mg/mL (~342.23 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (14.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (14.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (14.24 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (684.46 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)