ME2 tetramer decarboxylates MAL to PYR

Stable Identifier
Reaction [transition]
Homo sapiens
ME2:Mg2+ tetramer oxidatively decarboxylates MAL to PYR
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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 utilise 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+ 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
12962632 Crystal structures of substrate complexes of malic enzyme and insights into the catalytic mechanism

Yang, Z, Tong, L, Tao, X

Structure 2003
14596586 Structure and function of malic enzymes, a new class of oxidative decarboxylases

Tong, L, Chang, GG

Biochemistry 2003
23284632 Biophysical characterization of the dimer and tetramer interface interactions of the human cytosolic malic enzyme

Murugan, S, Hung, HC

PLoS ONE 2012
12121650 Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate

Lanks, CW, Yang, Z, Tong, L

Structure 2002
25202825 Human mitochondrial NAD(P)(+)-dependent malic enzyme participates in cutaneous melanoma progression and invasion

Huang, SM, Chiang, CP, Hung, HC, Chang, YL, Liu, GY, Gao, HW, Wang, WM, Ku, CF

J. Invest. Dermatol. 2015
1993674 Human NAD(+)-dependent mitochondrial malic enzyme. cDNA cloning, primary structure, and expression in Escherichia coli

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

J. Biol. Chem. 1991
7757881 Purification and properties of cytosolic and mitochondrial malic enzyme isolated from human brain

Bukato, G, Kochan, Z, SwierczyƄski, J

Int J Biochem Cell Biol 1995
27166188 The mechanisms of malic enzyme 2 in the tumorigenesis of human gliomas

Hsieh, CH, Huang, SM, Chang, YL, Hueng, DY, Cheng, CP, Huang, LC

Oncotarget 2016
Catalyst Activity

malate dehydrogenase (decarboxylating) (NAD+) activity of ME2:Mg2+ tetramer [mitochondrial matrix]

This event is regulated
Negatively by
Positively by
Orthologous Events
Cross References
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