AI Article Synopsis
- Tiancimycin (TNM) A is part of a group of complex natural products known for their potential as clinical drugs, with specific enzymes involved in their biosynthesis.
- The enzyme TnmL has been identified to perform two key hydroxylation reactions on TNM E, leading to the creation of TNM F and TNM C.
- TnmL shows a preference for certain substrates and has a unique role in the biosynthesis process by converting a shunt product (TNM G) back into the main production pathway for TNM A.
Article Abstract
Tiancimycin (TNM) A belongs to the anthraquinone-fused subfamily of enediyne natural products, and selected enediynes have been translated into clinical drugs. Previously, inactivation of in sp. CB03234 resulted in the accumulation of TNM B and TNM E, supporting the functional assignment of TnmL as a cytochrome P450 hydroxylase that catalyzes A-ring modification in TNM A biosynthesis. Herein, we report in vitro characterization of TnmL, revealing that (i) TnmL catalyzes two successive hydroxylations of TNM E, resulting in sequential production of TNM F and TNM C, (ii) TnmL shows a strict substrate preference, with the C-26 side chain playing a critical role in substrate binding, and (iii) TnmL demethylates the C-7 OCH group of TNM G, affording TNM F, thereby channeling the shunt product TNM G back into TNM A biosynthesis and representing a rare proofreading logic for natural product biosynthesis. These findings shed new insights into anthraquinone-fused enediyne biosynthesis.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532388 | PMC |
| http://dx.doi.org/10.1021/acschembio.1c00365 | DOI Listing |
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