Figure 2.

Oxygen‐dependent regulation of hypoxia‐induced factor (HIF) signaling. A) In normoxic environment, prolyl hydroxylase domain enzymes (PHDs) hydroxylate HIF‐1α subunits with production of carbon dioxide (CO₂) and succinate as byproducts. Hydroxylation requires α‐KG and oxygen (O₂) as substrates and is catalyzed by ferrous ions (Fe²⁺). The hydroxylated HIF‐1α subunits then undergo ubiquitination and degradation preventing nuclear translocation. B) In hypoxic conditions, there is an insufficient O₂ supply for extensive hydroxylation of HIF‐1α subunits avoiding degradation to translocate to the nucleus and complex with HIF‐1β to promote transcription.