Malic enzyme 2, mitochondrial (ME2)

Malic enzyme 2, mitochondrial (ME2) is a nuclear-encoded mitochondrial enzyme that catalyzes the oxidative decarboxylation of (S)-malate to pyruvate, concurrently reducing NAD+ or NADP+ to NADH or NADPH (UniProt P23368). It plays a pivotal role in linking the citric acid cycle with glutaminolysis and fatty acid synthesis, making it essential for the metabolic reprogramming observed in rapidly proliferating cancer cells (PubMed: 30160039). ME2 is frequently overexpressed in various malignancies, including pancreatic, lung, and breast cancers, where it supports redox homeostasis and mitochondrial biogenesis by acting as a sensor for fumarate (Cell Metab. 2021;33(5):1027-1041). Beyond oncology, genetic variants of ME2 are associated with susceptibility to idiopathic generalized epilepsy due to its involvement in the synthesis of the neurotransmitter GABA (Wikipedia; NCBI Gene ID: 4200). Therapeutic strategies targeting ME2 involve small-molecule inhibitors like Galloflavin or experimental leads such as NPD-389 and FLA, which aim to induce metabolic stress and activate p53-mediated senescence in tumor cells (PNAS 2023;120(23):e2216713120).

Other names

NAD-dependent malic enzyme, mitochondrialMalate dehydrogenase (oxaloacetate-decarboxylating)mNAD-MEODS1Pyruvic-malic carboxylaseMalic enzyme 2, NAD(+)-dependent, mitochondrial

Inhibition of the oxidative decarboxylation of malate to pyruvate, which reduces the production of NADPH and NADH, increases reactive oxygen species (ROS) levels, and disrupts mitochondrial metabolism and biogenesis in cancer cells.