| 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
|
| リソース情報 |
| ヒト・動物細胞 |
HL60 |
