Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases.
Pioneering work in the 1960s defined prolyl and lysyl hydroxylations as physiologically important oxygenase-catalyzed modifications in collagen biosynthesis; subsequent studies demonstrated that extracellular epidermal growth factor-like domains were hydroxylated at aspartyl and asparaginyl residues. More recent work on the hypoxia-sensing mechanism in animals has shown that prolyl and asparaginyl hydroxylation of the hypoxia-inducible transcription factor play central roles in sensing hypoxia, by regulating protein-protein interactions in an oxygen-dependent manner. The collective results imply that protein hydroxylation is more common than previously perceived. Most protein hydroxylases employ Fe(II) as a cofactor, and 2-oxoglutarate and oxygen as co-substrates. Related enzymes catalyze the demethylation of N(ɛ)-methyl lysine residues in histones and of N-methylated nucleic acids, as well as hydroxylation of 5-methyl cytosine in DNA and 5-methoxycarbonylmethyluridine at the wobble position of tRNA. The combination of new molecular biological and analytical techniques is likely to reveal further roles for oxygenase-mediated modifications to biomacromolecules.
Loenarz
Christoph
C
Chemistry Research Laboratory and The Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Schofield
Christopher J
CJ
D000818:Animals; D002384:Catalysis; D003094:Collagen / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008745:Methylation; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000378:metabolism*
D003094:Collagen; D006899:Mixed Function Oxygenases