2001 Fiscal Year Final Research Report Summary
Investigation of Target Molecules of Methylmercury Toxicity
| Project/Area Number |
12470091
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Public health/Health science
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| Research Institution | Tohoku University |
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Principal Investigator |
NAGANUMA Akira Tohoku University, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究科, 教授 (80155952)
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| Co-Investigator(Kenkyū-buntansha) |
FURUCHI Takemitsu Tohoku University, Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学研究科, 助手 (00302167)
MIURA Nobuhiko National Institute of Industrial Health, Researcher, 研究員 (20229644)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Methylmercury / Resistance / Yeast / GFAT / Cdc34 / Ubiquitin |
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| Research Abstract |
Methylmercury is a significant environmental contaminant that will continue to pose a great risk to human health. However, the biochemical mechanism responsible to methylmercury toxicity is not clearly identified. We have reported that L-glutamine:D-fructose-6-phosphate amidotransferase (GFAT) is a target molecule of methylmercury in the yeast. In the present study, the relationship between methylmercury toxicity and GFAT activity was examined in cultured human cells. In yeast, cytotoxicity of the methylmercury is remarkably reduced by overexpression of GFAT or by loading excess glucosamine-6phosphate which is a product of the GFAT reaction. However, the protective effect of loading of excess glucosamine-6-phosphate against methylmercury toxicity was not observed in HeLa cells. 293E cells overexpressing GFAT also hardly demonstrated resistance to methylmercury. These results suggest that GFAT may not be a target molecule of methylmercury at least in HeLa and 293E cells. Thus, we have s
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earched for other genes conferring methylmercury resistance by transforming a genomic library into Saccharomyces cerevisiae. We have identified CDC34 as a methylmercury resistance gene. CDC34 encodes one of the ubiquitin-conjugating enzymes that catalyze ubiquitin transfer onto substrate proteins, an important step for protein degradation via ubiquitin-proteasome pathway. To investigate the mechanism for reduction of the sensitivity of yeast to methylmercury by overexpression of CDC34, we examined the viability of yeast strains overexpressed various CDC34 mutants in the presence of methylmercury. Since CDC34 mutants, cdc34C95A, cdc34E109, D111, E113A or cdc341-170aa, which have been shown to have less or none ubiquitin-conjugating activity, failed to confer methylmercury resistance, ubiquitin-conjugating activity of Cdc34 seems to be essential for the resistance. Cdc34 has an important role not only in yeast but also in humans. These results suggested that ubiquitin-conjugating enzymes may play a critical role on methylmercury resistance in yeast. Cdc34 has an important role not only in yeast but also in humans. Less
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[Publications] Naganuma, A., Miura, N., Kaneko, S., Mishina, T., Hosoya, S., Miyairi, S., Furuchi, T. and Kuge, S.: "GFAT as a target molecule of methylmercury toxicity in Saccharomyces cerevisiae"FASEB J.. 14. 968-972 (2000)
Description
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