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1.  Phylogenomic identification of five new human homologs of the DNA repair enzyme AlkB 
BMC Genomics  2003;4:48.
Combination of biochemical and bioinformatic analyses led to the discovery of oxidative demethylation – a novel DNA repair mechanism catalyzed by the Escherichia coli AlkB protein and its two human homologs, hABH2 and hABH3. This discovery was based on the prediction made by Aravind and Koonin that AlkB is a member of the 2OG-Fe2+ oxygenase superfamily.
In this article, we report identification and sequence analysis of five human members of the (2OG-Fe2+) oxygenase superfamily designated here as hABH4 through hABH8. These experimentally uncharacterized and poorly annotated genes were not associated with the AlkB family in any database, but are predicted here to be phylogenetically and functionally related to the AlkB family (and specifically to the lineage that groups together hABH2 and hABH3) rather than to any other oxygenase family. Our analysis reveals the history of ABH gene duplications in the evolution of vertebrate genomes.
We hypothesize that hABH 4–8 could either be back-up enzymes for hABH1-3 or may code for novel DNA or RNA repair activities. For example, enzymes that can dealkylate N3-methylpurines or N7-methylpurines in DNA have not been described. Our analysis will guide experimental confirmation of these novel human putative DNA repair enzymes.
PMCID: PMC317286  PMID: 14667252
phylogenomics; bioinformatics; dealkylation; demethylation; dioxygenases
2.  Characterization of the cofactor-binding site in the SPOUT-fold methyltransferases by computational docking of S-adenosylmethionine to three crystal structures 
BMC Bioinformatics  2003;4:9.
There are several evolutionarily unrelated and structurally dissimilar superfamilies of S-adenosylmethionine (AdoMet)-dependent methyltransferases (MTases). A new superfamily (SPOUT) has been recently characterized on a sequence level and three structures of its members (1gz0, 1ipa, and 1k3r) have been solved. However, none of these structures include the cofactor or the substrate. Due to the strong evolutionary divergence and the paucity of experimental information, no confident predictions of protein-ligand and protein-substrate interactions could be made, which hampered the study of sequence-structure-function relationships in the SPOUT superfamily.
We used the computational docking program AutoDock to identify the AdoMet-binding site on the surface of three MTase structures. We analyzed the sequence divergence in two distinct lineages of the SPOUT superfamily in the context of surface features and preferred cofactor binding mode to propose specific function for the conserved residues.
Our docking analysis has confidently predicted the common AdoMet-binding site in three remotely related proteins structures. In the vicinity of the cofactor-binding site, subfamily-conserved grooves were identified on the protein surface, suggesting location of the target-binding/catalytic site. Functionally important residues were inferred and a general reaction mechanism, involving conformational change of a glycine-rich loop, was proposed.
PMCID: PMC153507  PMID: 12689347

Results 1-2 (2)