β-Methyltryptamine Provoking the Crucial Role of Strictosidine Synthase Tyr151-OH for Its Stereoselective Pictet-Spengler Reactions to Tryptoline-type Alkaloids

Haicheng Liu, Santosh Panjikar, Xiang Sheng, Yushi Futamura, Chenghua Zhang, Nana Shao, Hiroyuki Osada, Hongbin Zou*

*この研究の対応する著者

研究成果: Article査読

1 被引用数 (Scopus)

抄録

Strictosidine synthase (STR), the gate enzyme for monoterpenoid indole alkaloid biosynthesis, catalyzes the Pictet-Spengler reaction (PSR) of various tryptamine derivatives with secologanin assisted by "indole sandwich"stabilization. Continuous exploration with β-methyltryptamine (IPA) stereoselectively delivered the C6-methylstrictosidines and C6-methylvincosides by enzymatic and nonenzymatic PSR, respectively. Unexpectedly, the first "nonindole sandwich"binding mode was witnessed by the X-ray structures of STR1-ligand complexes. Site-directed mutagenesis revealed the critical cryptic role of the hydroxyl group of Tyr151 in IPA biotransformation. Further computational calculations demonstrated the adjustable IPA position in STR1 upon the binding of secologanin, and Tyr151-OH facilitates the productive PSR binding mode via an advantageous hydrogen-bond network. Further chemo-enzymatic manipulation of C6-methylvincosides successfully resulted in the discovered antimalarial framework (IC50 = 0.92 μM).

本文言語English
ページ(範囲)187-197
ページ数11
ジャーナルACS Chemical Biology
17
1
DOI
出版ステータスPublished - 2022 1月 21
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子医療

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