When oxygen levels are normal (normoxia, left), a PHD enzyme (green) can use molecular oxygen (O2), iron ions (Fe2+) and 2-oxogluterate (2-OG) to hydroxylate (ie, add an OH group to) two proline amino acids (P) on a HIFα protein. Hydroxylation destabilizes the HIFα protein, causing it to be degraded by the cell, and the genes involved in the hypoxic response of the cell are not expressed. When oxygen levels are low (hypoxia, right), the PHD enzyme is not able to hydroxylate the HIFα protein, so this protein can migrate into the nucleus and bind to a protein called ARNT. Together, they interact with hypoxia response elements (HREs) in the genome to activate the transcription of hypoxia response genes. ARNT: aryl hydrocarbon receptor nuclear translocator or hypoxic inducible factor-β (HIFβ); HIF: hypoxic inducible transcription factor; PHD: prolyl hydroxylase.