2-Oxoglutarate-Dependent Enzymes as Novel Therapeutic Targets in Diseases
2-oxoglutarate-dependent dioxygenases (2-OGDDs) are an enzyme family with ~70 members in human that share the same reaction mechanism but act on different substrate varying from proteins to DNA, RNA and fatty acids. 2-OGDDs require as cofactors a divalent metal (typically Fe2+), 2-oxoglutarate (2-OG) and O2, and a reducing agent (usually vitamin C) to support the reaction. 2-OGDDs include the collagen prolyl 4-hydroxylases (C-P4Hs), the hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also known as PHDs and EglNs), a transmembrane P4H (P4H-TM) and the hypoxia-inducible factor (HIF) asparaginyl hydroxylase FIH. Many 2-OGDDs act on chormatin structure as erasors, such as the DNA demethylating TETs and numerous histone lysine demethylases (KDMs).
2-OGDDs can be targeted with small molecule compounds, such as the HIF-P4H inhibitors that have advanced to final phase clinical trials for the treatment of anemia. We hypothesize that these inhibitors can in addition to anemia be used to treat ischemic, metabolic and inflammatory conditions. We also anticipate that other 2-OGDDs can be targeted with small molecule inhibitors to for example to treat cancer.
Last updated: 14.5.2020