Preparation of domoic acid analogues using a bioconversion system, and their toxicity in mice

Yukari Maeno, Yuichi Kotaki, Ryuta Terada, Masafumi Hidaka, Yuko Cho, Keiichi Konoki, Mari Yotsu-Yamashita

研究成果: Article査読

抄録

Domoic acid (1, DA), a member of the natural kainoid family, is a potent agonist of ionotropic glutamate receptors in the central nervous system. The chemical synthesis of DA and its derivatives requires considerable effort to establish a pyrrolidine ring containing three contiguous stereocenters. Recently, a biosynthetic cyclase for DA, DabC, was identified. This enzyme cyclizes the linear precursor of isodomoic acid A (IA) to IA, a bioactive DA analogue. In this study, we developed a bioconversion system to obtain DA analogues from linear substrates prepared by simple chemical synthesis using DabC expressed inEscherichia coli,in vivo. Three IA analogues with various substitutions at the C7′-geranyl terminus were prepared using this system: two minor natural analogues, 7′-methyl-IA (5) and 7′-hydroxy-IA (6), and one new unnatural analogue, 7′-amide-IA (7). In addition, the toxicity of these DA analogues in mice was examined by intracerebroventricular injection. Most of the mice injected with5(3 nmol) and6(3 nmol) did not show any adverse symptoms, whereas the mice injected with7(3 nmol) showed typical symptoms induced by DA (1, 0.7 nmol) and IA (2, 3 nmol). These results suggest that the 7′-carbonyl group in the side chain of IA (2) is crucial for its toxicity. The docking studies of DA, IA (2),5,6, and7to GluK1 supported these results.

本文言語English
ページ(範囲)7894-7902
ページ数9
ジャーナルOrganic and Biomolecular Chemistry
19
36
DOI
出版ステータスPublished - 2021 9 28

ASJC Scopus subject areas

  • 生化学
  • 物理化学および理論化学
  • 有機化学

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