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).
Indolethylamine N-methyltransferase (INMT) is involved in the methylation of dimethyl selenide (Me2Se) into trimethylselenonium (Me3Se+) in tandem with S-adenosylmethionine (AdoMet) transforming into S-adenosylhomocysteine (AdoHcy). This reaction is inferred from the event in mouse (Mozier et al. 1988).
All characterized lysine demethylases other than KDM1A belong to the jumonjiC domain (JmjC) containing family.The JmjC KDMs are members of the Cupin superfamily of mononuclear Fe (II) dependent oxygenases, which are characterized by the presence of a double-stranded beta-helix core fold. The JmjC KDMs require 2 oxoglutarate (2 OG) and molecular oxygen as co substrates, producing, along with formaldehyde, succinate and carbon dioxide. This hydroxylation based mechanism does not require a protonatable lysine epsilon-amine group and consequently JmjC containing demethylases are able to demethylate tri , di and monomethylated lysines.
KDM5A-D (JARID1A-D) catalyse the demethylation of di- or tri-methylated lysine-5 of histone H3 (H3K4Me2/3) (Christensen et al. 2007, Klose et al. 2007, Lee et al. 2007, Secombe et al. 2007, Seward et al. 2007, Iwase et al. 2007).
JMJD6 catalyses demethylation of mono- or di-methylated arginine-3 of histone H3 (H3R2Me1/2) and arginine-4 of histone H4 (H4R3Me1/2) (Chang et al. 2007). Non-histone substrates of JMJD6 arginine demethylation have also been reported (Poulard et al. 2014, Lawrence et al. 2014). Subsequent to its characterization as an arginine demethylase, JMJD6 was reported to be a lysine hydroxylase (Webby et al 2009).
JMJD6 catalyses demethylation of mono- or di-methylated arginine-3 of histone H3 (H3R2Me1/2) and arginine-4 of histone H4 (H4R3Me1/2) (Chang et al. 2007). Non-histone substrates of JMJD6 arginine demethylation have also been reported (Poulard et al. 2014, Lawrence et al. 2014). Subsequent to its characterization as an arginine demethylase, JMJD6 was reported to be a lysine hydroxylase (Webby et al 2009).
H4R3me2s is a direct binding target for the DNA methyltransferase DNMT3A, which interacts through the ADD domain containing the PHD motif. Loss of the H4R3me2s mark through short hairpin RNA–mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation (Zhao et al. 2009).