Malic enzyme 2 (ME2)

Malic enzyme 2 (ME2) is a mitochondrial homotetrameric enzyme that catalyzes the oxidative decarboxylation of L-malate to pyruvate, utilizing NAD+ or NADP+ as cofactors [4, 7]. It serves as a critical metabolic link between the tricarboxylic acid (TCA) cycle and pyruvate production, while simultaneously generating reducing equivalents like NADH and NADPH essential for energy production and redox homeostasis [1, 5]. In various malignancies, including leukemia and glioblastoma, ME2 is frequently upregulated to support the high metabolic demands of rapid cell proliferation and to protect against oxidative stress [3, 10, 12]. Inhibition of ME2 has been shown to impair mitochondrial respiration, deplete ATP, and increase reactive oxygen species (ROS), leading to cellular senescence or apoptosis [5, 14, 15]. Beyond its role in oncology, genetic variations in the ME2 gene are associated with neurological disorders such as idiopathic generalized epilepsy and schizophrenia [4, 11]. Current therapeutic research focuses on allosteric inhibitors like embonic acid and MDSA, which target the enzyme's regulatory sites to disrupt metabolic flux in cancer cells [7, 17]. Additionally, ME2 is a key component of synthetic lethality strategies in tumors harboring ME1 deletions [1, 21].

Other names

NAD-dependent malic enzyme, mitochondrialMalate dehydrogenase (oxaloacetate-decarboxylating)Malic enzyme 2, mitochondrialODS1m-NAD-ME

Allosteric inhibition of enzymatic activity by binding to the fumarate-binding site or dimer interface, leading to the disruption of mitochondrial energy metabolism, reduction of NADPH levels, and induction of oxidative stress-mediated apoptosis or senescence.