Prolyl 4-hydroxylases, master regulators of the hypoxia response

A decrease in oxygenation is a life-threatening situation for most organisms. An evolutionarily conserved efficient and rapid hypoxia response mechanism activated by a hypoxia-inducible transcription factor (HIF) is present in animals ranging from the simplest multicellular phylum Placozoa to humans. In humans, HIF induces the expression of more than 100 genes that are required to increase oxygen delivery and to reduce oxygen consumption. As its name indicates HIF is found at protein level only in hypoxic cells, whereas in normoxia, it is degraded by the proteasome pathway. Prolyl 4-hydroxylases, enzymes that require oxygen in their reaction, are the cellular oxygen sensors regulating the stability of HIF. In normoxia, 4-hydroxyproline residues formed in the α-subunit of HIF by these enzymes lead to its ubiquitination by the von Hippel-Lindau E3 ubiquitin ligase and immediate destruction in proteasomes thus preventing the formation of a functional HIF αβ dimer. Prolyl 4-hydroxylation is inhibited in hypoxia, facilitating the formation of the HIF dimer and activation of its target genes, such as those for erythropoietin and vascular endothelial growth factor. This review starts with a summary of the molecular and catalytic properties and individual functions of the four HIF prolyl 4-hydroxylase isoenzymes. Induction of the hypoxia response via inhibition of the HIF prolyl 4-hydroxylases may provide a novel therapeutic target in the treatment of hypoxia-associated diseases. The current status of studies aiming at such therapeutic approaches is introduced in the final part of this review.