Pathway retrofitting yields insights into the biosynthesis of anthraquinone-fused enediynes
Anthraquinone-fused enediynes (AQEs) are renowned for their distinctive molecular architecture, reactive enediyne warhead, and potent anticancer activity. Although the first members of AQEs, i.e., dynemicins, were discovered three decades ago, how their nitrogen-containing carbon skeleton is sy...
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| Main Authors: | , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
2022
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/155780 |
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| Institution: | Nanyang Technological University |
| Language: | English |
| Summary: | Anthraquinone-fused enediynes (AQEs) are renowned
for their distinctive molecular architecture, reactive
enediyne warhead, and potent anticancer activity. Although the
first members of AQEs, i.e., dynemicins, were discovered three
decades ago, how their nitrogen-containing carbon skeleton is
synthesized by microbial producers remains largely a mystery. In
this study, we showed that the recently discovered sungeidine
pathway is a “degenerative” AQE pathway that contains upstream
enzymes for AQE biosynthesis. Retrofitting the sungeidine
pathway with genes from the dynemicin pathway not only restored
the biosynthesis of the AQE skeleton but also produced a series of
novel compounds likely as the cycloaromatized derivatives of
chemically unstable biosynthetic intermediates. The results suggest a cascade of highly surprising biosynthetic steps leading to the
formation of the anthraquinone moiety, the hallmark C8−C9 linkage via alkyl−aryl cross-coupling, and the characteristic epoxide
functionality. The findings provide unprecedented insights into the biosynthesis of AQEs and pave the way for examining these
intriguing biosynthetic enzymes. |
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