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Trends Biochem Sci. 2011 Jan;36(1):7-18. doi: 10.1016/j.tibs.2010.07.002. Epub 2010 Aug 20.

Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases.

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Chemistry Research Laboratory and The Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.


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.

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