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HIF hydroxylases - enzymes for oxygen

The cellular response to a lack of oxygen revolves around a transcription factor termed hypoxiainducible factor (HIF), which regulates processes such as energy metabolism, angiogenesis and apoptosis. When oxygen is present, prolyl and asparaginyl hydroxylases use it to hydroxylate HIF, targeting the transcription factor for degradation and inactivation, respectively. In a Commentary on p. 3041, Norma Masson and Peter Ratcliffe discuss studies that are helping us to understand these interesting enzymes, which are members of a 2-oxoglutarate (2-OG)-dependent oxygenase superfamily. The prolyl hydroxylases (PHD1-PHD3) hydroxylate two proline residues within LxxLAP motifs in the HIF oxygen-dependent-degradation domain (ODD). This allows the residues to bind to a pocket within the von-Hippel-Lindau (pVHL) tumour suppressor protein - the substrate-recognition component of the E3 ubiquitin ligase complex responsible for proteolysis of HIF. The asparaginyl hydroxylases (FIHs) hydroxylate an asparagine residue within the HIF C-terminal transactivation domain (C-TAD). This prevents it from recruiting co-activators such as p300, blocking HIF-dependent transcription. The direct incorporation of molecular oxygen at the site of hydroxylation makes these enzymes well suited to oxygen sensing. Moreover, they require multiple co-factors and co-substrates, which probably contributes to their regulatory potential.

Related articles in JCS:

HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O₂ levels

Norma Masson and Peter J. Ratcliffe
JCS 2003 116: 3041-3049. [Abstract] [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content