Biosynthesis of the Immunosuppressant (-)-FR901483

Biosynthesis of the Immunosuppressant (-)-FR901483

We report characterization of the biosynthetic pathway of the potent immunosuppressant (-)-FR901483 (1) through heterologous expression and enzymatic assays. The biosynthetic logic to form the azatricyclic alkaloid is consistent with those proposed in biomimetic syntheses and involves aza-spiro annu...

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Veröffentlicht in:Journal of the American Chemical Society 2021-01, Vol.143 (1), p.132-136
Hauptverfasser: Zhang, Zhuan, Tamura, Yui, Tang, Mancheng, Qiao, Tianzhang, Sato, Michio, Otsu, Yoshihiro, Sasamura, Satoshi, Taniguchi, Masatoshi, Watanabe, Kenji, Tang, Yi
Format: Artikel
Sprache:eng
Schlagworte:
Ascomycota - genetics
Ascomycota - metabolism
Chemistry
Chemistry, Multidisciplinary
Enzymes - genetics
Enzymes - metabolism
Fungal Proteins - genetics
Fungal Proteins - metabolism
Immunosuppressive Agents - metabolism
Multigene Family
Organophosphorus Compounds - metabolism
Physical Sciences
Science & Technology
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Zusammenfassung:We report characterization of the biosynthetic pathway of the potent immunosuppressant (-)-FR901483 (1) through heterologous expression and enzymatic assays. The biosynthetic logic to form the azatricyclic alkaloid is consistent with those proposed in biomimetic syntheses and involves aza-spiro annulation of dityrosyl-piperazine to form a ketoaldehyde intermediate, followed by regioselective aldol condensation, stereoselective ketoreduction, and phosphorylation. A possible target of 1 is proposed based on the biosynthetic studies.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.0c12352