2006 Fiscal Year Final Research Report Summary
Study on respiratory enzyme complex I based on the organic synthesis of acetogenin analogues
| Project/Area Number |
17380073
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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 |
Bioproduction chemistry/Bioorganic chemistry
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| Research Institution | Kyoto University |
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Principal Investigator |
MIYOSHI Hideto Kyoto University, Graduate School of Agriculture, Associate Professor, 農学研究科, 助教授 (20190829)
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| Co-Investigator(Kenkyū-buntansha) |
KITA Kiyoshi The University of Tokyo, Graduate School of Medicine, Professor, 医学系研究科, 教授 (90134444)
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| Project Period (FY) |
2005 – 2006
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| Keywords | mitochondria / respiratory inhibitor / acetogenin / complex I |
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| Research Abstract |
Natural antibiotic acetogenins are very potent and structurally unique inhibitors of mitochondrial complex I. In this study, we planed the following three subjects in order to get insight into the function of mitochondrial complex I using originally synthesized acetogenin analogues, in which various functionalities are built.
1) We will synthesize a photoreactive acetogenin to identify acetogenin-binding subunit by photoaffinity technique.
2) To know the function of the alkyl spacer of acetogenins, we will synthesize gamma-lactone and THF moieties separately, which possess azido or alkyne groups. We will examine whether the two moieties can bind in the enzyme by so called "Click Chemistry".
3) Since Δlac-acetogenins which have no lactone ring were shown to be a new class of inhibitors of complex I, we will further modify this class of inhibitors to develop novel molecular probes for the research of complex I.
For the first subject, we succeeded to prepared a good photoaffinity probe possessing aryl diazirine ring as a photoreactive group. Using this probe, we proved that the ND1 subunit is the binding-subunit of acetogenin.
For the second subject, we tried to incubate various pairs of lactone and THF moieties under various experimental conditions, but no pairs elicited strong inhibitory effect, meaning that no pairs made [3+2]-cycloaddition at enzyme-bound state.
For the third subject, on the basis of competitive replacement text using the photoaffinity probe described above, we got further strong experimental evidence indicating that the binding site of Δlac-acetogenins differ from that of natural-type acetogenin.
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