Inhibition of 2-oxoglutarate dependent oxygenases

Abstract

2-Oxoglutarate (2OG) dependent oxygenases are ubiquitous iron enzymes that couple substrate oxidation to the conversion of 2OG to succinate and carbon dioxide. In humans their roles include collagen biosynthesis, fatty acid metabolism, DNA repair, RNA and chromatin modifications, and hypoxic sensing. Commercial applications of 2OG oxygenase inhibitors began with plant growth retardants, and now extend to a clinically used pharmaceutical compound for cardioprotection. Several 2OG oxygenases are now being targeted for therapeutic intervention for diseases including anaemia, inflammation and cancer. In this critical review, we describe studies on the inhibition of 2OG oxygenases, focusing on small molecules, and discuss the potential of 2OG oxygenases as therapeutic targets (295 references).

TET-catalyzed 5-methylcytosine hydroxylation is dynamically regulated by metabolites

“…While the biological function and catalytic mechanism of TET enzymes are being extensively investigated, much less is currently known about their regulation. TET proteins are the members of Fe(II)/α-ketoglutarate (α-KG)-dependent dioxygenases, which require Fe(II) as a metal cofactor and α-KG as a co-substrate [8,9]. In various types of tumors, pathological accumulation of three metabolites, 2-HG, succinate and fumurate, that share structural similarity with α-KG, results in a competitive inhibition of α-KGdependent TET activity, leading to a hypermethylation phenotype [10,11].…”

Mitochondrial metabolites extend lifespan

“…As mentioned earlier, 2,4‐PDA is an α‐ketoglutarate mimetic that inhibits multiple α‐ketoglutarate‐dependent hydroxylases (Rose et al ., 2011) (Table S3). 2,4‐PDA binds to the active site of these enzymes with low micromolar affinity, and competitively with respect to α‐ketoglutarate (Majamaa et al ., 1984).…”

“…FIH works by preventing HIF‐1α from interacting with the p300 transcriptional co‐activator protein (Hewitson et al ., 2002). Inhibition of FIH by endogenous citric acid cycle metabolites, including pyruvate, has been previously reported (Rose et al ., 2011). C. elegans lacks FIH, and so if the three BCKAs were exclusively targeting FIH in 3T3‐L1 cells, this would provide a simple explanation for why there was no effect of these compounds on HIF‐1::myc stabilization in worms.…”

Fighting Fire with Fire in Cancer

“…Mechanistic studies of D2HG have focused on its competitive inhibition of 2-OG-dependent dioxygenases (2OGD), which use αKG as a cosubstrate [36]. In mammalian cells, there are more than 60 2OGD involved in collagen biosynthesis, fatty acid metabolism, DNA repair, RNA and chromatin modifications, and hypoxia detection [51]. The general enzymatic reaction performed by 2OGD converts αKG to succinate and CO 2 , and requires oxygen, ascorbate, and iron as cofactors [51].…”

“…In mammalian cells, there are more than 60 2OGD involved in collagen biosynthesis, fatty acid metabolism, DNA repair, RNA and chromatin modifications, and hypoxia detection [51]. The general enzymatic reaction performed by 2OGD converts αKG to succinate and CO 2 , and requires oxygen, ascorbate, and iron as cofactors [51]. D2HG has been shown in vitro to competitively inhibit 2OGD [52], and the high concentration of D2HG measured in cells and tissues of IDH-mutant tumors makes it very likely that D2HG impairs the activity of this class of enzymes in vivo as well [36].…”