Dihydrolipoamide dehydrogenase (DLD) (DLD)

Dihydrolipoamide dehydrogenase (DLD), also known as the E3 subunit, is a mitochondrial flavoprotein enzyme essential for the function of several multi-enzyme complexes involved in energy metabolism, including the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes [1, 6]. It catalyzes the reversible oxidation of dihydrolipoamide to lipoamide using NAD+ as an electron acceptor, thereby linking the tricarboxylic acid (TCA) cycle to the electron transport chain [8, 11]. Historically, the enzyme purified from pig heart has served as the primary biochemical model for understanding its structure and catalytic mechanism due to its high abundance and stability in that tissue [15, 16]. In addition to its metabolic role, DLD possesses moonlighting functions as a protease and a diaphorase, the latter of which can generate or scavenge reactive oxygen species (ROS) [1, 10]. DLD is recognized as a therapeutic target in oncology, particularly in melanoma and multiple myeloma, where its inhibition by drugs like devimistat or bortezomib disrupts cancer cell metabolism and promotes cell death [9, 11, 12]. Mutations in the DLD gene lead to DLD deficiency, a severe metabolic disorder characterized by lactic acidosis and neurological impairment [6, 10].

Other names

Dihydrolipoyl dehydrogenaseLipoamide dehydrogenaseE3 componentGCSLLADPHE3Pig heart dihydrolipoamide dehydrogenase

Inhibition of the E3 subunit of alpha-ketoacid dehydrogenase complexes, disrupting the TCA cycle and energy metabolism, or modulating ROS production and Nrf2 signaling pathways.