ArticleProceedings of the National Academy of Sciences of the United States of America2009
Selective oxidation of carbolide C-H bonds by an engineered macrolide P450 mono-oxygenase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed.
- Article
- Late-stage modification of bioactive compounds: Improving druggability through efficient molecular editing.Acta pharmaceutica Sinica. B · 2024Review
- Nitric oxide synthase-guided genome mining identifies a cytochrome P450 enzyme for olefin nitration in bacterial specialized metabolism.Synthetic and systems biotechnology · 2024Article
- Epoxyalcohol Synthase Branch of Lipoxygenase Cascade.Current issues in molecular biology · 2024Review
- Unnatural activities and mechanistic insights of cytochrome P450 PikC gained from site-specific mutagenesis by non-canonical amino acids.Nature communications · 2023Article
- Cytochrome P450Angewandte Chemie (International ed. in English) · 2022Article
- A Unique P450 Peroxygenase System Facilitated by a Dual-Functional Small Molecule: Concept, Application, and Perspective.Antioxidants (Basel, Switzerland) · 2022Review
- Ru(II)-diimine complexes and cytochrome P450 working hand-in-hand.Journal of inorganic biochemistry · 2020Review
- Molecular Basis of Iterative C─H Oxidation by TamI, a Multifunctional P450 monooxygenase from the Tirandamycin Biosynthetic Pathway.ACS catalysis · 2020Article
- Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications.The Journal of biological chemistry · 2020Review
- The complete genome sequence of the nitrile biocatalyst Rhodocccus rhodochrous ATCC BAA-870.BMC genomics · 2020Article
- Positioning-Group-Enabled Biocatalytic Oxidative Dearomatization.ACS central science · 2019Article
- Review
- Selective CH bond functionalization with engineered heme proteins: new tools to generate complexity.Current opinion in chemical biology · 2019Review
- Production of pikromycin using branched chain amino acid catabolism in Streptomyces venezuelae ATCC 15439.Journal of industrial microbiology & biotechnology · 2018Article
- Synthesis of Diverse 11- and 12-Membered Macrolactones from a Common Linear Substrate Using a Single Biocatalyst.ACS central science · 2017Article
- Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function.Natural product reports · 2017Review
- Engineering of versatile redox partner fusions that support monooxygenase activity of functionally diverse cytochrome P450s.Scientific reports · 2017Article
- Selective oxidation of aliphatic C-H bonds in alkylphenols by a chemomimetic biocatalytic system.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Chemoenzymatic Total Synthesis and Structural Diversification of Tylactone-Based Macrolide Antibiotics through Late-Stage Polyketide Assembly, Tailoring, and C-H Functionalization.Journal of the American Chemical Society · 2017Article
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Authors and funding
6 authors.
Funding
Abstract
Regio- and stereoselective oxidation of an unactivated C-H bond remains a central challenge in organic chemistry. Considerable effort has been devoted to identifying transition metal complexes, biological catalysts, or simplified mimics, but limited success has been achieved. Cytochrome P450 mono-oxygenases are involved in diverse types of regio- and stereoselective oxidations, and represent a promising biocatalyst to address this challenge. The application of this class of enzymes is particularly significant if their substrate spectra can be broadened, selectivity controlled, and reactions catalyzed in the absence of expensive heterologous redox partners. In this study, we engineered a macrolide biosynthetic P450 mono-oxygenase PikC (PikC(D50N)-RhFRED) with remarkable substrate flexibility, significantly increased activity compared to wild-type enzyme, and self-sufficiency. By harnessing its unique desosamine-anchoring functionality via a heretofore under-explored "substrate engineering" strategy, we demonstrated the ability of PikC to hydroxylate a series of carbocyclic rings linked to the desosamine glycoside via an acetal linkage (referred to as "carbolides") in a regioselective manner. Complementary analysis of a number of high-resolution enzyme-substrate cocrystal structures provided significant insights into the function of the aminosugar-derived anchoring group for control of reaction site selectivity. Moreover, unexpected biological activity of a select number of these carbolide systems revealed their potential as a previously unrecorded class of antibiotics.
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