title: Origin and evolution of peptide-modifying dioxygenases and identification of the wybutosine hydroxylase/hydroperoxidase.
abstract: Unlike classical 2-oxoglutarate and iron-dependent dioxygenases, which include several nucleic acid modifiers, the structurally similar jumonji-related dioxygenase superfamily was only known to catalyze peptide modifications. Using comparative genomics methods, we predict that a family of jumonji-related enzymes catalyzes wybutosine hydroxylation/peroxidation at position 37 of eukaryotic tRNAPhe. Identification of this enzyme raised questions regarding the emergence of protein- and nucleic acid-modifying activities among jumonji-related domains. We addressed these with a natural classification of DSBH domains and reconstructed the precursor of the dioxygenases as a sugar-binding domain. This precursor gave rise to sugar epimerases and metal-binding sugar isomerases. The sugar isomerase active site was exapted for catalysis of oxygenation, with a radiation of these enzymes in bacteria, probably due to impetus from the primary oxygenation event in Earth's history. 2-Oxoglutarate-dependent versions appear to have further expanded with rise of the tricarboxylic acid cycle. We identify previously under-appreciated aspects of their active site and multiple independent innovations of 2-oxoacid-binding basic residues among these superfamilies. We show that double-stranded β-helix dioxygenases diversified extensively in biosynthesis and modification of halogenated siderophores, antibiotics, peptide secondary metabolites and glycine-rich collagen-like proteins in bacteria. Jumonji-related domains diversified into three distinct lineages in bacterial secondary metabolism systems and these were precursors of the three major clades of eukaryotic enzymes. The specificity of wybutosine hydroxylase/peroxidase probably relates to the structural similarity of the modified moiety to the ancestral amino acid substrate of this superfamily.
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: Lakshminarayan M
authors.initials: LM
authors.lastname: Iyer
authors.forename: Saraswathi
authors.initials: S
authors.lastname: Abhiman
authors.forename: Robson F
authors.initials: RF
authors.lastname: de Souza
authors.forename: L
authors.initials: L
authors.lastname: Aravind
mesh_terms: D000595:Amino Acid Sequence; D001419:Bacteria / Q000201:enzymology; D020134:Catalytic Domain; D049308:Dioxygenases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056890:Eukaryota / Q000201:enzymology; D019143:Evolution, Molecular; D005798:Genes, Bacterial; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D009705:Nucleosides / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D010544:Peroxidases / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012360:RNA, Transfer, Phe / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D009705:Nucleosides; D010455:Peptides; D012360:RNA, Transfer, Phe; C467591:wybutosine; D006899:Mixed Function Oxygenases; D010544:Peroxidases; D049308:Dioxygenases