Structure-Agnostic Bioactivity-Driven Combinatorial Biosynthesis Reveals New Antidiabetic and Anticancer Triterpenoids.

Although combinatorial biosynthesis can dramatically expand the chemical structures of bioactive natural products to identify molecules with improved characteristics, progress in this direction has been hampered by the difficulty in isolating and characterizing the numerous produced compounds. This challenge could be overcome with improved designs that enable the analysis of the bioactivity of the produced metabolites ahead of the time-consuming isolation procedures. Herein, we showcase a structure-agnostic bioactivity-driven combinatorial biosynthesis workflow that introduces bioactivity assessment as a selection-driving force to guide iterative combinatorial biosynthesis rounds towards enzyme combinations with increasing bioactivity.

Oxetane Ring Formation in Taxol Biosynthesis Is Catalyzed by a Bifunctional Cytochrome P450 Enzyme.

Taxol is a potent drug used in various cancer treatments. Its complex structure has prompted extensive research into its biosynthesis. However, certain critical steps, such as the formation of the oxetane ring, which is essential for its activity, have remained unclear.

Widespread biosynthesis of 16-carbon terpenoids in bacteria.

Terpenoids are the most diverse group of specialized metabolites with numerous applications. Their biosynthesis is based on the five-carbon isoprene building block and, as a result, almost all terpenoids isolated to date are based on backbones that contain multiples of five carbon atoms. Intrigued by the discovery of an unusual bacterial terpenoid with a 16-carbon skeleton, here we investigate whether the biosynthesis of 16-carbon terpenoids is more widespread than this single example.

Structurally Diverse Cytotoxic Polyphenols from .

Thirty-five diverse polyphenols, belonging to seven structure classes, were isolated from , a medicinal and edible plant sampled from Laos. The structures of nine new compounds, gargarcilones A-I (-, -, , , and ), were established using spectroscopic, X-ray diffraction, and experimental and calculated ECD methods. Additionally, we revised the stereochemical assignment of cochinchinoxanthone and cochinchinoxanthone C.

Biosynthesis and biotechnological production of the anti-obesity agent celastrol.

Obesity is a major health risk still lacking effective pharmacological treatment. A potent anti-obesity agent, celastrol, has been identified in the roots of Tripterygium wilfordii. However, an efficient synthetic method is required to better explore its biological utility.

Expanding the terpene biosynthetic code with non-canonical 16 carbon atom building blocks.

Humankind relies on specialized metabolites for medicines, flavors, fragrances, and numerous other valuable biomaterials. However, the chemical space occupied by specialized metabolites, and, thus, their application potential, is limited because their biosynthesis is based on only a handful of building blocks. Engineering organisms to synthesize alternative building blocks will bypass this limitation and enable the sustainable production of molecules with non-canonical chemical structures, expanding the possible applications.