Reactome | ME2 tetramer decarboxylates MAL to PYR

ME2 tetramer decarboxylates MAL to PYR

Stable Identifier

R-HSA-9012268

Type

Reaction [transition]

Species

Homo sapiens

Compartment

mitochondrial matrix

Synonyms

ME2:Mg2+ tetramer oxidatively decarboxylates MAL to PYR

ReviewStatus

5/5

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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, Swierczyński, 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