In the normal cell with active VHL protein, HIF alpha is regulated by hydroxylation in the presence of oxygen. When iron, 2-oxoglutarate and oxygen are present, HIF is inactivated by HIF hydroxylases. Hydroxylation of HIF creates a binding site for pVHL (the protein product of the VHL gene).[10] pVHL directs the polyubiquitylation of HIF1A, ensuring that this protein will be degraded by the proteasome.