3 ステロールおよびトリテルペン合成酵素活性中心の親和性標識(口頭発表の部)
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概要
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Enzymatic Cyclization of squalene and oxidosqualene lead to sterols and triterpenes in bacteria, fungi, plants, and animals. The cyclases for these reactions catalyze formation and stabilization of polycyclic carbocations and direct the enzyme-specific, templated formation of new carbon-carbon bonds in regio- and stereochemically defined manner. Studies of these enzymes are now progressing rapidly and promise to reveal the intimate three-dimensional structural details of the enzyme-catalyzed processes. In particular, the development of mechanism-based irreversible inhibitors, photoactivatable inhibitors, and numerous substrate analogs have helped to unravel the stepwise events occurring in the catalytic sites of these enzymes by covalent modification of specific amino acid residues. Here we report affinity labeling of vertebrate oxidosqualene: lanosterol cyclase and bacterial squalene: hopene cyclase by three active-site probes developed in our laboratory; (i) [^3H(3S)29-methylidene-2,3-oxidosqualene (29-MOS), (ii) [^3H]18-thia-2,3-oxidosqualene, and (iii) [^3H]Ro 48-8071. The mechanism-based irreversible inhibitors and the photoactivatable active-site targeted inhibitor have afforded important insights into the cyclization mechanism. The next generation of results will place the mechanistic understanding into a structural context, and the roles for specific active site residues will be elucidated through peptide mapping and crystallographic studies.
- 天然有機化合物討論会の論文
- 1998-08-31