2-oxoglutarate-dependent dioxygenase family as a molecular sensor for cellular oxygen and metabolic sensing

Hypoxic condition is formed in our body when the oxygen demand exceeds the supply. Hypoxic response is triggered under such condition to maintain homeostasis. However, it had been unclear for a long time how cells sense changes of surrounding oxygen environment and activate hypoxic response. Studies of molecular machinery responding to hypoxia largely progressed in the mid 90's after the identification of Hypoxia-Inducible Factor, HIF. Then, the prolyl hydroxylase domain-containing protein (PHD)-HIF pathway was characterized as a central pathway for cells to monitor the decrease in oxygen concentration and maintain cellular function in hypoxia. PHD is recognized as one of the cellular oxygen sensors because it requires oxygen molecule for its enzymatic activity. Importantly, there is a large enzyme family named 2-oxoglutarate-dependent dioxygenase (2OGDD), which require O2, Fe2+, 2-oxoglutarate as co-factors like PHD. In this review, we will overview how 2OGDDs operate, and what are their roles in pathological situation. We also discuss possible direction of how we can establish drugs to target 2OGDDs.