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

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2011, Vol.36 (1), p.7-18
• Main Authors: Loenarz, Christoph, Schofield, Christopher J.
• Format: Article
• Language: English
• Subjects: analytical methods; Animals; biosynthesis; Catalysis; collagen; Collagen - metabolism; cytosine; DNA; histones; Humans; Hydroxylation; hypoxia; iron; lysine; Methylation; Mixed Function Oxygenases - chemistry; Mixed Function Oxygenases - metabolism; new combination; oxygen; oxygenases; protein-protein interactions; transcription factors; transfer RNA
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2010.07.002

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.