1993 Fiscal Year Final Research Report Summary
Structural Analysis of Fungal Lanosterol Demethylase for Developing High-selective Antifungal Agents
| Project/Area Number |
03671075
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Mukogawa Women's Universtiy |
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Principal Investigator |
YOSHIDA Yuzo Mukogawa Women's Univ., Fac. Pharm. Sci, . Associate Professor, 薬学部, 助教授 (70085281)
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| Co-Investigator(Kenkyū-buntansha) |
AOYAMA Yuri Mukogawa Women's Univ., Fac. Pharm. Sci, . Asistant, 薬学部, 助手 (00158718)
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| Project Period (FY) |
1991 – 1993
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| Keywords | P450 / Azole anitifungal agent / Fungi / Mammalia / Target specificity / Lanosterol / Substrate recognition / Sterol demethylase inhibitor |
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| Research Abstract |
Aim of porject : Azole antifungals are potent inhibitors of fungal P450(14DM). Therefore, high selectivity for fungal P450(14DM) without any inhibitory effect on mammalian P450s is expected for them. The aim of this project is to assume structures necessary for azole antifungals to have high selectivity for fungal P450(14DM) through structural analysis of the substrate recognition site of P450(14DM).
Results : (1) Fungal P450(14DM) showed structure-specific interaction with the 3 beta-hydroxyl group, DELTA8-lanostene skeleton and the terminal part of the sterol side chain. (2) The sterol ring of the substrate might be holded in the space over pyrrole C and heme iron and the side chain might be situated on the amino acid residue(s) covering pyrrole A.(3) Rat and yeast P450(14DM)s showed different recognition for the structure of the sterol side chain. These findings suggest a possibility that azole compounds interacting with the side-chain recognition site of P450(14DM) may show high selectivity for the fungal enzyme. This possibility was confirmed by the following comparative experimennts on the effects of the azole compounds having isoprenoid moiety on rat and yeast P450(14DM)s. (4) The azole compound bearing geranyl moiety that corresponds to the lanosterol side chain showed potent inhibition by interacting with the side-chain recognition site of these enzymes. (5) Decrement in the inhibitory effect by the substitution of the geranyl moiety with longer or shorter isoprenoids was far greater in the rat enzyme than in the yeast one. (6) They act weak inhibitors for the rat liver 7-ethoxycoumarin deethylase P450. These lines of evidence suggest a possibility that the azole compounds interacting with the side-chain recognition part of P450(14DM) show high selectivity for the fungal enzyme.
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