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. 2021 Jan 13;143(1):132-136.
doi: 10.1021/jacs.0c12352. Epub 2020 Dec 29.

Biosynthesis of the Immunosuppressant (-)-FR901483

Zhuan Zhang, Yui Tamura  1 , Mancheng Tang, Tianzhang Qiao, Michio Sato  1 , Yoshihiro Otsu  2 , Satoshi Sasamura  2 , Masatoshi Taniguchi  2 , Kenji Watanabe  1 , Yi Tang
Affiliations

Biosynthesis of the Immunosuppressant (-)-FR901483

Zhuan Zhang et al. J Am Chem Soc. .

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Structures of (−)-FR901483 1 and related (+)-TAN1251C.
Figure 2.
Figure 2.
Characterization of FR901483 biosynthesis. A) The frz cluster encodes a NRPS (A-T-R, A, adenylation, T, thiolation; R, reductase) FrzA and tailoring enzymes; B) Biosynthesis of 7 from l-Tyr.
Figure 3.
Figure 3.
Reconstitution of the biosynthesis of 1. (A) LC-MS analysis of products profiles of heterologous expression of different combinations of frz genes; (B) LC-MS analysis of in vitro assay from 11 to 1; (C) Proposed pathway of 7 to 1. Note: Peak labeled with * is identified by selected ion monitoring but is unrelated to the frz pathway.
See this image and copyright information in PMC

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