Oxoglutarate dehydrogenase (OGDH)

Oxoglutarate dehydrogenase (OGDH) is the E1 component of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a mitochondrial enzyme that catalyzes the rate-limiting step of the tricarboxylic acid (TCA) cycle [1, 5]. The enzyme performs the oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA, a process strictly dependent on the cofactor thiamine pyrophosphate (TPP) binding to the E1 subunit [2]. OGDH plays a central role in cellular energy production and links the TCA cycle with amino acid metabolism, particularly glutamate [1]. Reduced activity of this enzyme is associated with neurodegenerative diseases like Alzheimer's and Parkinson's, where metabolic failure contributes to pathology [2]. In cancer, OGDH is often targeted by inhibitors like devimistat to exploit the metabolic vulnerabilities of tumor cells [4]. Therapeutic strategies involve either supplementing TPP to restore enzyme function or using competitive inhibitors at the TPP-binding site to disrupt pathological metabolic flux [3, 4].

Other names

Alpha-ketoglutarate dehydrogenase2-oxoglutarate dehydrogenaseE1 component of the alpha-ketoglutarate dehydrogenase complexAKGDHOGDH

The mechanism of action involves the binding of thiamine pyrophosphate (TPP) to the E1 subunit to facilitate the decarboxylation of alpha-ketoglutarate. Therapeutic agents may act as TPP mimetics or precursors to enhance enzyme activity in deficiency states, or as competitive inhibitors at the TPP-binding site to disrupt metabolic flux in cancer cells [2, 4].