Abstract
House-cleaning enzymes protect cells from the adverse effects of noncanonical metabolic chemical compounds. The Escherichia coli nucleotide phosphatase YjjG (B4374, JW4336) functions as a house-cleaning phosphatase in vivo. YjjG protects the cell against noncanonical pyrimidine derivatives such as 5-fluoro-2'-deoxyuridine (5-FdUridine), 5-fluorouridine, 5-fluoroorotic acid (5-FOA), 5-fluorouracil, and 5-aza-2'-deoxycytidine. YjjG prevents the incorporation of potentially mutagenic nucleotides into DNA as shown for 5-bromo-2'-deoxyuridine (BrdU). Its enzymatic activity in vitro towards noncanonical 5-fluoro-2'-deoxyuridine monophosphate (5-FdUMP) is higher than towards canonical thymidine monophosphate (dTMP). The closest homolog in humans, HDHD4, does not show a protective effect against noncanonical nucleotides, excluding an involvement of HDHD4 in resistance against noncanonical nucleotides used for cancer chemotherapy. The substrate spectrum of YjjG suggests that its in vivo substrates are noncanonical pyrimidine derivatives, which might also include oxidized nucleobases such as 5-formyluracil and 5-hydroxyuracil.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Azacitidine / analogs & derivatives
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Azacitidine / chemistry
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Azacitidine / pharmacology
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Bromodeoxyuridine / pharmacology
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DNA Damage
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Decitabine
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Deoxyuridine / chemistry
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Deoxyuridine / pharmacology
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Escherichia coli / drug effects
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Escherichia coli / genetics
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Escherichia coli / metabolism*
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Escherichia coli Proteins / genetics
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Escherichia coli Proteins / metabolism*
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Fluorouracil / chemistry
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Fluorouracil / pharmacology
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Models, Biological
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Molecular Structure
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Mutation
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N-Glycosyl Hydrolases / genetics
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N-Glycosyl Hydrolases / metabolism*
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Nucleotidases / genetics
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Nucleotidases / metabolism*
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Orotic Acid / analogs & derivatives
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Orotic Acid / chemistry
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Orotic Acid / pharmacology
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Substrate Specificity
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Thymidine Monophosphate / chemistry
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Thymidine Monophosphate / pharmacology
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Uridine / analogs & derivatives
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Uridine / chemistry
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Uridine / pharmacology
Substances
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Escherichia coli Proteins
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Thymidine Monophosphate
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5-fluorouridine
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Orotic Acid
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Decitabine
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5-fluoroorotic acid
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Nucleotidases
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YjjG protein, E coli
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nucleotidase
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N-Glycosyl Hydrolases
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Bromodeoxyuridine
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Azacitidine
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Fluorouracil
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Deoxyuridine
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Uridine