論文 - 詳細
| RRC ID | 74510 |
|---|---|
| 著者 | Liu H, Panjikar S, Sheng X, Futamura Y, Zhang C, Shao N, Osada H, Zou H. |
| タイトル | β-Methyltryptamine Provoking the Crucial Role of Strictosidine Synthase Tyr151-OH for Its Stereoselective Pictet-Spengler Reactions to Tryptoline-type Alkaloids. |
| ジャーナル | ACS Chem Biol |
| Abstract |
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). |
| 巻・号 | 17(1) |
| ページ | 187-197 |
| 公開日 | 2022-1-21 |
| DOI | 10.1021/acschembio.1c00844 |
| PMID | 34994203 |
| MeSH | Alkaloids* / chemistry Alkaloids* / metabolism Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Carbolines* / chemistry Carbolines* / metabolism Carbon-Nitrogen Lyases* / genetics Carbon-Nitrogen Lyases* / metabolism Catalytic Domain Cell Survival / drug effects HL-60 Cells Humans Models, Molecular Molecular Structure Protein Binding Protein Conformation Tryptamines* / chemistry Tryptamines* / metabolism p-Hydroxyamphetamine |
| IF | 4.434 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.2 |
| リソース情報 | |
| ヒト・動物細胞 | HL60 |