ArticleProceedings of the National Academy of Sciences of the United States of America2017
Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 36 citations in OpenAlex.
- Complete Pathway Refactoring and Combinatorial Biosynthesis of Anthracyclines for Modulation of Histone Eviction and DNA Damage Bioactivities.Angewandte Chemie (International ed. in English) · 2026Article
- Molecular basis for the biosynthetic divergence of anthracyclines kosinostatin and chartreusin.Chemical science · 2026Article
- Discovery of natural products that modulate signaling in patient-derived cells.RSC chemical biology · 2026Article
- Three-Enzyme Cascade Catalyzes Conversion of Auramycinone to Resomycin in Chartreusin Biosynthesis.ACS chemical biology · 2025Article
- Diverse Combinatorial Biosynthesis Strategies for C-H Functionalization of Anthracyclinones.ACS synthetic biology · 2024Article
- Development of a drug discovery approach from microbes with a special focus on isolation sources and taxonomy.The Journal of antibiotics · 2023Review
- Actinorhodin Biosynthesis Terminates with an Unprecedented Biaryl Coupling Reaction.Angewandte Chemie (International ed. in English) · 2023Article
- CytA, a reductase in the cytorhodin biosynthesis pathway, inactivates anthracycline drugs inCommunications biology · 2019Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ranking among the most effective anticancer drugs, anthracyclines represent an important family of aromatic polyketides generated by type II polyketide synthases (PKSs). After formation of polyketide cores, the post-PKS tailoring modifications endow the scaffold with various structural diversities and biological activities. Here we demonstrate an unprecedented four-enzyme-participated hydroxyl regioisomerization process involved in the biosynthesis of kosinostatin. First, KstA15 and KstA16 function together to catalyze a cryptic hydroxylation of the 4-hydroxyl-anthraquinone core, yielding a 1,4-dihydroxyl product, which undergoes a chemically challenging asymmetric reduction-dearomatization subsequently acted by KstA11; then, KstA10 catalyzes a region-specific reduction concomitant with dehydration to afford the 1-hydroxyl anthraquinone. Remarkably, the shunt product identifications of both hydroxylation and reduction-dehydration reactions, the crystal structure of KstA11 with bound substrate and cofactor, and isotope incorporation experiments reveal mechanistic insights into the redox dearomatization and rearomatization steps. These findings provide a distinguished tailoring paradigm for type II PKS engineering.
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