ArticleNature chemistry2026
Exploring bacterial cytochrome P450s for selective activation of aliphatic C-H bonds in pentacyclic triterpenoids.
Article in Nature chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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12 authors.
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Abstract
Selective activation of aliphatic C-H bonds in polycyclic terpenoids offers a potent strategy for exploring diverse chemical space in drug design, yet challenges persist in achieving site- and diastereoselectivity, especially with increasing structural complexity. Here we report a bioinformatics-driven terpene-P450 discovery strategy to develop bacterial cytochrome P450s for selective activation of aliphatic C-H bonds in structurally intricate pentacyclic triterpenoids (PTs). The identified ApPT demonstrated elegant diastereoselectivity and broad substrate tolerance, facilitating a chemo-enzymatic platform to explore the chemical space of PTs at previously inaccessible sites. Protein crystallization and computational analysis reveal the mechanism of the preliminary C-H bond activation selectivity of ApPT towards various PTs, particularly an example of enzymatic C7-to-C15 relay oxidation mediated by 1,5-hydrogen atom transfer. This work offers ApPT as a valuable biocatalyst to explore the chemical space of PTs via aliphatic C-H bond activation, demonstrating the advantage of our biocatalyst-discovery strategy for the late-stage diversification of polycyclic terpenoids.
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