SDT1/SSM1, a multicopy suppressor of S-II null mutant, encodes a novel pyrimidine 5'-nucleotidase.
SDT1 (suppressor of disruption of TFIIS 1, YGL224c, also known as SSM1, suppressor of S-II null mutant 1) is Saccharomyces cerevisiae gene identified as a multicopy suppressor of 6-azauracil sensitivity in a null mutant of the transcription elongation factor S-II. We found that overproduction of SDT1 caused hyposensitivity to not only 6-azauracil but also 5-fluorouracil and 5-fluorocytosine. This hyposensitivity was limited to pyrimidine derivatives, and no effect was observed for non-pyrimidine drugs including such clinically used anti-fungal drugs as amphotericin B and fluconazole. Purified recombinant SDT1 protein specifically dephosphorylated 5'-UMP and 5'-CMP. These results suggested that SDT1 conferred pyrimidine-specific hyposensitivity by dephosphorylating active metabolites of 6- or 5-modified pyrimidines, i.e. 6- or 5-modified UMP. This is the first description of a highly specific pyrimidine 5'-nucleotidase in S. cerevisiae.
Nakanishi
Toshiyuki
T
Discovery Research Laboratories, Daiichi Pharmaceutical Company, Ltd., Edogawa-ku, Tokyo 134-8630, Japan. nakanfnt@daichipharm.co.jp
Sekimizu
Kazuhisa
K
D015720:5'-Nucleotidase / Q000235:genetics*; D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000378:metabolism; D015725:Fluconazole / Q000494:pharmacology; D005437:Flucytosine / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics* / Q000502:physiology*; D008969:Molecular Sequence Data; D009708:Nucleotidases; D010766:Phosphorylation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics* / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D013379:Substrate Specificity
D000935:Antifungal Agents; D005656:Fungal Proteins; D011994:Recombinant Proteins; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D000666:Amphotericin B; D015725:Fluconazole; D005437:Flucytosine; D009708:Nucleotidases; D015720:5'-Nucleotidase; C489269:SDT1 protein, S cerevisiae; D005472:Fluorouracil