ArticleJournal of the American Chemical Society2014
Systematic domain swaps of iterative, nonreducing polyketide synthases provide a mechanistic understanding and rationale for catalytic reprogramming.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 61 citations in OpenAlex.
- Alternative splicing-induced thioesterase domain deficiency drives the production of natural orsellinic acid derivatives with a pantetheine moiety in nonreducing polyketide synthases.Synthetic and systems biotechnology · 2027Article
- Granaticin biosynthesis and engineering: mechanistic understanding, production bottlenecks, and computational opportunities.World journal of microbiology & biotechnology · 2026Review
- Extending the starter-unit selection of a collaborating non-reducing polyketide synthase through rational domain swaps.RSC advances · 2026Article
- The divergence of DHN-derived melanin pathways in Metarhizium robertsii.World journal of microbiology & biotechnology · 2024Article
- Combinatorial biosynthesis for the engineering of novel fungal natural products.Communications chemistry · 2024Review
- The Ketosynthase Domain Controls Chain Length in Mushroom Oligocyclic Polyketide Synthases.Chembiochem : a European journal of chemical biology · 2023Article
- Sea Urchin Polyketide Synthase SpPks1 Produces the Naphthalene Precursor to Echinoderm Pigments.Journal of the American Chemical Society · 2022Article
- Structures and function of a tailoring oxidase in complex with a nonribosomal peptide synthetase module.Nature communications · 2022Article
- Pathway engineering in yeast for synthesizing the complex polyketide bikaverin.Nature communications · 2020Article
- Probing Selectivity and Creating Structural Diversity Through Hybrid Polyketide Synthases.Angewandte Chemie (International ed. in English) · 2020Article
- The Mosaic Architecture of NRPS-PKS in the Arbuscular Mycorrhizal FungusFrontiers in microbiology · 2020Article
- Late-Stage Conversion of Diphenylphosphonate to Fluorophosphonate Probes for the Investigation of Serine Hydrolases.Cell chemical biology · 2019Article
- Modulation of polyketide biosynthetic pathway of the endophytic fungus,Phytochemistry letters · 2018Article
- Biochemical characterization of the minimal domains of an iterative eukaryotic polyketide synthase.The FEBS journal · 2018Article
- Exploring Fungal Polyketide C-Methylation through Combinatorial Domain Swaps.ACS chemical biology · 2018Article
- The architectures of iterative type I PKS and FAS.Natural product reports · 2018Review
- The structural organization of substrate loading in iterative polyketide synthases.Nature chemical biology · 2018Article
- In trans hydrolysis of carrier protein-bound acyl intermediates by CitA during citrinin biosynthesis.Chemical communications (Cambridge, England) · 2017Article
- Polyketide mimetics yield structural and mechanistic insights into product template domain function in nonreducing polyketide synthases.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Functional and Structural Analysis of Programmed C-Methylation in the Biosynthesis of the Fungal Polyketide Citrinin.Cell chemical biology · 2017Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
Iterative, nonreducing polyketide synthases (NR-PKSs) are multidomain enzymes responsible for the construction of the core architecture of aromatic polyketide natural products in fungi. Engineering these enzymes for the production of non-native metabolites has been a long-standing goal. We conducted a systematic survey of in vitro "domain swapped" NR-PKSs using an enzyme deconstruction approach. The NR-PKSs were dissected into mono- to multidomain fragments and recombined as noncognate pairs in vitro, reconstituting enzymatic activity. The enzymes used in this study produce aromatic polyketides that are representative of the four main chemical features set by the individual NR-PKS: starter unit selection, chain-length control, cyclization register control, and product release mechanism. We found that boundary conditions limit successful chemistry, which are dependent on a set of underlying enzymatic mechanisms. Crucial for successful redirection of catalysis, the rate of productive chemistry must outpace the rate of spontaneous derailment and thioesterase-mediated editing. Additionally, all of the domains in a noncognate system must interact efficiently if chemical redirection is to proceed. These observations refine and further substantiate current understanding of the mechanisms governing NR-PKS catalysis.
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