Meta-Biol

• Pathways

One hallmark of cancer is altered cellular metabolism. Malic enzymes (MEs) are a family of homotetrameric enzymes that catalyse the reversible oxidative decarboxylation of L-malate to pyruvate, with a simultaneous reduction of NAD(P)+ to NAD(P)H. As MEs generate NADPH and NADH, they may play dual roles in energy production and reductive biosynthesis. Humans possess three ME isoforms; ME1 is cytosolic and utilises NADP+, ME3 is mitochondrial and can utilise NADP+ and ME2 is mitochondrial and can utililse either NAD+ or NADP+ (Chang & Tong 2003).

Mitochondrial NAD-dependent malic enzyme (ME2, aka m-NAD(P)-ME) oxidatively decarboxylates (s)-malate (MAL) to pyruvate (PYR) and CO2 using NAD+ (or NADP+) as cofactor (Loeber et al. 1991, Tao et al. 2003). ME2 exists as a dimer of dimers and requires a divalent metal such as Mg2+ for catalysis (Chang & Tong 2003, Murugan & Hung 2012). Unlike the other MEs, ME2's enzymatic activity can be allosterically activated by fumarate (FUMA) and inhibited by ATP (Yang et al. 2002). ME2 could play a critical role in cutaneous melanoma progression, the most life-threatening neoplasm of the skin. Targeting ME2 could be a novel approach to inhibiting melanoma cell proliferation and growth (Chang et al. 2015). ME2 has also been demonstrated to be involved in glioblastoma multiforme (GBM) growth, invasion and migration. Inhibition of ME2 could potentially be therapeutic in the treatment of GBM (Cheng et al. 2016).