ME2:Mg2+ tetramer oxidatively decarboxylates MAL to PYR

Stable Identifier
R-HSA-9012268
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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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).

Literature References
PubMed ID Title Journal Year
14596586 Structure and function of malic enzymes, a new class of oxidative decarboxylases

Chang, GG, Tong, L

Biochemistry 2003
12962632 Crystal structures of substrate complexes of malic enzyme and insights into the catalytic mechanism

Tao, X, Yang, Z, Tong, L

Structure 2003
1993674 Human NAD(+)-dependent mitochondrial malic enzyme. cDNA cloning, primary structure, and expression in Escherichia coli

Loeber, G, Infante, AA, Maurer-Fogy, I, Krystek, E, Dworkin, MB

J. Biol. Chem. 1991
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
malate dehydrogenase (decarboxylating) (NAD+) activity of ME2:Mg2+ tetramer [mitochondrial matrix]
Physical Entity
Activity
This event is regulated
Orthologous Events
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Rhea
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Created