Abstract
GyrI-like proteins are widely distributed in prokaryotes and eukaryotes, and recognized as small-molecule binding proteins. Here, we identify a subfamily of these proteins as cyclopropanoid cyclopropyl hydrolases (CCHs) that can catalyze the hydrolysis of the potent DNA-alkylating agents yatakemycin (YTM) and CC-1065. Co-crystallography and molecular dynamics simulation analyses reveal that these CCHs share a conserved aromatic cage for the hydrolytic activity. Subsequent cytotoxic assays confirm that CCHs are able to protect cells against YTM. Therefore, our findings suggest that the evolutionarily conserved GyrI-like proteins confer cellular protection against diverse xenobiotics via not only binding, but also catalysis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkylating Agents / chemistry*
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Alkylating Agents / pharmacology
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Animals
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Bacterial Physiological Phenomena*
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Binding Sites
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Biocatalysis*
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Cell Line, Tumor
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Crystallography, X-Ray
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DNA / metabolism
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DNA Topoisomerases, Type II / metabolism
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Drug Resistance, Bacterial / physiology*
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Duocarmycins
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Escherichia coli / physiology
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Escherichia coli Proteins / metabolism
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Humans
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Hydrolases / chemistry
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Hydrolases / genetics
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Hydrolases / metabolism*
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Hydrolysis
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Indoles / chemistry
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Indoles / pharmacology
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Inhibitory Concentration 50
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Jurkat Cells
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Mice
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Microbial Sensitivity Tests
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Molecular Dynamics Simulation
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Repressor Proteins / metabolism
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Sequence Homology, Amino Acid
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Streptomyces / physiology
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Xenobiotics / chemistry
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Xenobiotics / pharmacology
Substances
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Alkylating Agents
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Duocarmycins
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Escherichia coli Proteins
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Indoles
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Pyrroles
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Recombinant Proteins
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Repressor Proteins
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SbmC protein, E coli
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Xenobiotics
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yatakemycin
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CC 1065
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DNA
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Hydrolases
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DNA Topoisomerases, Type II