ME2 Gene (Malic Enzyme 2): Function, Expression, Mutations, and Disease Associations

The ME2 gene encodes the mitochondrial NAD-dependent malic enzyme, a homotetrameric protein that catalyzes the oxidative decarboxylation of malate to pyruvate, producing NADH and CO2. This reaction is a critical node connecting the tricarboxylic acid (TCA) cycle, glycolysis, and lipogenesis. ME2 is widely expressed and plays a pivotal role in cellular metabolism, particularly in proliferating cells and cancer, where it supports NADPH production (via a secondary reaction) and pyruvate supply for biosynthesis. Mutations in ME2 are associated with a rare form of epileptic encephalopathy (DEE) and have been implicated in tumor suppression and cancer metabolism.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Pyruvate metabolism

• Tricarboxylic acid (TCA) cycle

• Gluconeogenesis

• Insulin secretion regulation

• Cancer metabolism (Warburg effect)

ME2 is a 584-amino acid mitochondrial protein that forms a homotetramer. It catalyzes the reversible oxidative decarboxylation of L-malate to pyruvate, using NAD+ as a cofactor and producing NADH and CO2. The enzyme requires a divalent metal ion (Mn2+ or Mg2+) for activity. Structurally, it consists of an N-terminal mitochondrial targeting sequence, a central domain that binds the nucleotide cofactor, and a C-terminal domain involved in substrate binding and tetramerization. ME2 plays a central role in metabolic reprogramming, particularly in cancer cells, where it can contribute to the production of pyruvate for the TCA cycle and NADPH for biosynthesis and redox balance.