Dimethyl 2-ketoglutarate:Physiological effects and Electrochemical behaviour

Dimethyl 2-ketoglutarate (DKG), a cell membrane-permeable precursor of a key metabolic intermediate, a-ketoglutarate (a-KG), known for its ability to rescue glutamine deficiency, transiently stabilized HIF-1a by inhibiting activity of the HIF prolyl hydroxylase domain-containing protein, PHD2.¹

Physiological effects

Dimethyl 2-ketoglutarate is an esterified form of the citric acid cycle intermediate α-ketoglutarate.

1. It increases intracellular levels of α-ketoglutarate and decreases intracellular ATP levels in U2OS human osteosarcoma cells cultured in complete- or nutrient-free media when used at a concentration of 5 mM.

2. Dimethyl 2-ketoglutarate inhibits autophagy and decreases in intracellular levels of acetyl-CoA in serum- and nutrient-deprived cells.

3. It decreases cardiomyocyte hypertrophy in a mouse model of cardiac pressure overload induced by thoracic aortic constriction when administered at a dose of 300 mg/kg. Dimethyl 2-ketoglutarate reduces serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and hepatic fibrosis in a rat model of liver fibrosis induced by carbon tetrachloride (CCl4).

Electrochemical behaviour

The electrochemical behaviour of dimethyl-2-oxoglutarate (MOG), a key intermediate in the Krebs cycle and an important nitrogen transporter in the metabolic pathways in biological processes, was investigated by cyclic voltammetry, square wave voltammetry and differential pulse voltammetry using a glassy carbon electrode. The reduction of MOG is an irreversible diffusion-controlled process that occurs in a cascade mechanism.

For electrolytes with pH <3.0 and pH >7.0 one peak occurred and for 3.0 < pH < 8.0 two peaks corresponding to consecutive charge transfer reactions were observed. The effects of scan rate, concentration and pH of the electrolyte solution were monitored, and both peaks were found to shift cathodically with the increase in pH. DPV measurements allowed the determination of the number of electrons and protons i.e., one electron and one proton, involved in the reduction mechanism of MOG. Based upon the results obtained a reduction mechanism was proposed and the observed waves were attributed to the hydroxylation of the keto group of MOG to form dimethyl-2-hydroxyglutarate.

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