The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases.
BACKGROUND
Protein fold recognition using sequence profile searches frequently allows prediction of the structure and biochemical mechanisms of proteins with an important biological function but unknown biochemical activity. Here we describe such predictions resulting from an analysis of the 2-oxoglutarate (2OG) and Fe(II)-dependent oxygenases, a class of enzymes that are widespread in eukaryotes and bacteria and catalyze a variety of reactions typically involving the oxidation of an organic substrate using a dioxygen molecule.


RESULTS
We employ sequence profile analysis to show that the DNA repair protein AlkB, the extracellular matrix protein leprecan, the disease-resistance-related protein EGL-9 and several uncharacterized proteins define novel families of enzymes of the 2OG-Fe(II) oxygenase superfamily. The identification of AlkB as a member of the 2OG-Fe(II) oxygenase superfamily suggests that this protein catalyzes oxidative detoxification of alkylated bases. More distant homologs of AlkB were detected in eukaryotes and in plant RNA viruses, leading to the hypothesis that these proteins might be involved in RNA demethylation. The EGL-9 protein from Caenorhabditis elegans is necessary for normal muscle function and its inactivation results in resistance against paralysis induced by the Pseudomonas aeruginosa toxin. EGL-9 and leprecan are predicted to be novel protein hydroxylases that might be involved in the generation of substrates for protein glycosylation.


CONCLUSIONS
Here, using sequence profile searches, we show that several previously undetected protein families contain 2OG-Fe(II) oxygenase fold. This allows us to predict the catalytic activity for a wide range of biologically important, but biochemically uncharacterized proteins from eukaryotes and bacteria.
Aravind
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National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA. aravind@ncbi.nlm.nih.gov
Koonin
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EV
D000595:Amino Acid Sequence; D000818:Animals; D029742:Caenorhabditis elegans Proteins; D019295:Computational Biology; D017124:Conserved Sequence; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D019992:Databases as Topic; D019143:Evolution, Molecular; D020224:Expressed Sequence Tags; D015801:Helminth Proteins / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism*; D008562:Membrane Glycoproteins; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010105:Oxygenases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D064828:Prolyl Hydroxylases; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011509:Proteoglycans / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017385:Sequence Homology; D012984:Software
D029742:Caenorhabditis elegans Proteins; C403074:Egl-9 protein, C elegans; D015801:Helminth Proteins; D007656:Ketoglutaric Acids; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D064828:Prolyl Hydroxylases; C485657:P3H1 protein, human; D042926:Cytochrome P-450 CYP4A