Malic enzyme 2, NAD-dependent, mitochondrial (ME2)

Malic enzyme 2 (ME2) is a mitochondrial NAD-dependent (and partially NADP-dependent) oxidative decarboxylase that catalyzes the conversion of L-malate to pyruvate and CO2, generating NADH (or NADPH), which is essential for ATP production and maintaining cellular redox balance. ME2 operates as a homotetramer and features unique allosteric regulation through activators (fumarate) and inhibitors (ATP, specific small molecules). It is involved in key metabolic pathways, including cellular respiration, glutaminolysis, and redox control, with a particularly important role in tumor metabolism and proliferation. ME2 has emerged as a promising anticancer target owing to its upregulation in cancer and its role in supporting tumor cell growth and survival. Notable inhibitors like MDSA, EA, and NPD389 have been developed and structurally characterized, functioning through distinct allosteric or kinetic mechanisms. Manipulation of ME2 impacts the NAD+/NADH ratio, cellular energy output, and oxidative stress response, underlining its significance in both normal mitochondrial function and disease.

Other names

ME2NAD-dependent malic enzyme, mitochondrialMalate dehydrogenase (oxaloacetate-decarboxylating)ODS1NAD-MEpyruvic-malic carboxylase

Allosteric inhibition at the fumarate-binding site (MDSA, EA): These inhibitors bind to an allosteric site at the dimer interface, locking ME2 in the inactive open conformation and reducing cellular respiration and ATP synthesis. Uncompetitive and mixed-type inhibition (NPD389): NPD389 is an uncompetitive inhibitor for NAD+ and a mixed-type inhibitor for L-malate, binding rapidly and reducing ME2 activity.