ArticleJournal of the American Chemical Society2022
Data Science-Driven Analysis of Substrate-Permissive Diketopiperazine Reverse Prenyltransferase NotF: Applications in Protein Engineering and Cascade Biocatalytic Synthesis of (-)-Eurotiumin A.
Article in Journal of the American Chemical Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 37 citations in OpenAlex.
- Sustainable Biocatalytic Cascades: A Versatile Tool in the Synthesis of Natural Products With Therapeutic Potential.Chembiochem : a European journal of chemical biology · 2026Review
- Discovery of unprecedented prenylated indole piperazines and pyrazines through cryptic biosynthetic gene cluster heterologous expression.Natural products and bioprospecting · 2026Article
- Facile Synthesis of Non-Proteinogenic Sulfur-Containing Cyclic Dipeptides and Their Structure-Antioxidant Activity Relationship.Chemistry, an Asian journal · 2026Article
- Engineering a Biosynthetic Pathway to Produce (+)-Brevianamides A and B.ACS catalysis · 2025Article
- The Mutually Inspiring Biological and Chemical Synthesis of Fungal Bicyclo[2.2.2]diazaoctane Indole Alkaloids.Chemical reviews · 2025Review
- Directed Evolution of a Modular Polyketide Synthase Thioesterase for Generation of a Hybrid Macrocyclic Ring System.ACS catalysis · 2025Article
- Characterization and structural analysis of a versatile aromatic prenyltransferase for imidazole-containing diketopiperazines.Nature communications · 2025Article
- Article
- Supramolecular Catalyzed Cascade Reduction of Azaarenes Interrogated via Data Science.Journal of the American Chemical Society · 2024Article
- Advances in the total synthesis of bis- and tris-indole alkaloids containing N-heterocyclic linker moieties.Natural product reports · 2024Review
- Discovery of Uncommon Tryptophan-Containing Diketopiperazines fromJournal of natural products · 2024Article
- Prenylation of aromatic amino acids and plant phenolics by an aromatic prenyltransferase from Rasamsonia emersonii.Applied microbiology and biotechnology · 2024Article
- Boosted Enzyme Activity via Encapsulation within Metal-Organic Frameworks with Pores Matching Enzyme Size and Shape.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations.Beilstein journal of organic chemistry · 2024Review
- Chemoenzymatic Synthesis of 13-Oxoverruculogen.Journal of the American Chemical Society · 2023Article
- Using Data Science for Mechanistic Insights and Selectivity Predictions in a Non-Natural Biocatalytic Reaction.Journal of the American Chemical Society · 2023Article
- Structure-guided Mutagenesis Reveals the Catalytic Residue that Controls the Regiospecificity of C6-Indole Prenyltransferases.ChemCatChem · 2023Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Prenyltransfer is an early-stage carbon-hydrogen bond (C-H) functionalization prevalent in the biosynthesis of a diverse array of biologically active bacterial, fungal, plant, and metazoan diketopiperazine (DKP) alkaloids. Toward the development of a unified strategy for biocatalytic construction of prenylated DKP indole alkaloids, we sought to identify and characterize a substrate-permissive C2 reverse prenyltransferase (PT). As the first tailoring event within the biosynthesis of cytotoxic notoamide metabolites, PT NotF catalyzes C2 reverse prenyltransfer of brevianamide F. Solving a crystal structure of NotF (in complex with native substrate and prenyl donor mimic dimethylallyl S-thiolodiphosphate (DMSPP)) revealed a large, solvent-exposed active site, intimating NotF may possess a significantly broad substrate scope. To assess the substrate selectivity of NotF, we synthesized a panel of 30 sterically and electronically differentiated tryptophanyl DKPs, the majority of which were selectively prenylated by NotF in synthetically useful conversions (2 to >99%). Quantitative representation of this substrate library and development of a descriptive statistical model provided insight into the molecular origins of NotF's substrate promiscuity. This approach enabled the identification of key substrate descriptors (electrophilicity, size, and flexibility) that govern the rate of NotF-catalyzed prenyltransfer, and the development of an "induced fit docking (IFD)-guided" engineering strategy for improved turnover of our largest substrates. We further demonstrated the utility of NotF in tandem with oxidative cyclization using flavin monooxygenase, BvnB. This one-pot,
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