Figure 4

Different model-based explanations for the effect of the PHD hydroxylation reaction on the HIF response. (A) The PHD hydroxylation of HIF-1α protein requires molecular oxygen (O₂), iron (Fe²⁺), 2-oxoglutarate (2OG) and ascorbate (Asc) as reactants, producing succinate (Suc) and carbon dioxide (CO₂). (B) In the presence of abundant PHD and hydroxylation cofactors, there is a step decrease in prolyl-hydroxylated HIF (HIF-1α-POH) with decreasing oxygen. However, this decrease is linear under limited PHD2 or cofactors[25]. (C) Increasing the ratio of succinate to PHD leads to increased succinate inhibition of PHD from negative feedback (A), resulting in decreased prolyl-hydroxylated HIF[28].