ArticleJournal of the American Chemical Society2012
Interrogation of global active site occupancy of a fungal iterative polyketide synthase reveals strategies for maintaining biosynthetic fidelity.
Article in Journal of the American Chemical Society, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 48 citations in OpenAlex.
- Basidiomycete non-reducing polyketide synthases function independently of SAT domains.Fungal biology and biotechnology · 2023Article
- The Ketosynthase Domain Controls Chain Length in Mushroom Oligocyclic Polyketide Synthases.Chembiochem : a European journal of chemical biology · 2023Article
- Article
- 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
- Inversion of Extender Unit Selectivity in the Erythromycin Polyketide Synthase by Acyltransferase Domain Engineering.ACS chemical biology · 2017Article
- Analysis of the Sequences, Structures, and Functions of Product-Releasing Enzyme Domains in Fungal Polyketide Synthases.Frontiers in microbiology · 2017Article
- Diversity-Oriented Combinatorial Biosynthesis of Hybrid Polyketide Scaffolds from Azaphilone and Benzenediol Lactone Biosynthons.Organic letters · 2016Article
- Assembly line termination in cylindrocyclophane biosynthesis: discovery of an editing type II thioesterase domain in a type I polyketide synthase.Chemical science · 2015Article
- Starter unit flexibility for engineered product synthesis by the nonreducing polyketide synthase PksA.ACS chemical biology · 2015Article
- Aflatoxin and deconstruction of type I, iterative polyketide synthase function.Natural product reports · 2014Review
- Systematic domain swaps of iterative, nonreducing polyketide synthases provide a mechanistic understanding and rationale for catalytic reprogramming.Journal of the American Chemical Society · 2014Article
- Review
- Rational domain swaps reveal insights about chain length control by ketosynthase domains in fungal nonreducing polyketide synthases.Organic letters · 2014Article
- Biochemical determination of enzyme-bound metabolites: preferential accumulation of a programmed octaketide on the enediyne polyketide synthase CalE8.Journal of the American Chemical Society · 2013Article
- Probing the selectivity and protein·protein interactions of a nonreducing fungal polyketide synthase using mechanism-based crosslinkers.Chemistry & biology · 2013Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Nonreducing iterative polyketide synthases (NR-PKSs) are responsible for assembling the core of fungal aromatic natural products with diverse biological properties. Despite recent advances in the field, many mechanistic details of polyketide assembly by these megasynthases remain unknown. To expand our understanding of substrate loading, polyketide elongation, cyclization, and product release, active site occupancy and product output were explored by Fourier transform mass spectrometry using the norsolorinic acid anthrone-producing polyketide synthase, PksA, from the aflatoxin biosynthetic pathway in Aspergillus parasiticus. Here we report the simultaneous observation of covalent intermediates from all catalytic domains of PksA from in vitro reconstitution reactions. The data provide snapshots of iterative catalysis and reveal an underappreciated editing function for the C-terminal thioesterase domain beyond its recently established synthetic role in Claisen/Dieckmann cyclization and product release. The specificity of thioesterase catalyzed hydrolysis was explored using biosynthetically relevant protein-bound and small molecule acyl substrates and demonstrated activity against hexanoyl and acetyl, but not malonyl. Processivity of polyketide extension was supported by the inability of a nonhydrolyzable malonyl analog to trap products of intermediate chain lengths and by the detection of only fully extended species observed covalently bound to, and as the predominant products released by, PksA. High occupancy of the malonyl transacylase domain and fast relative rate of malonyl transfer compared to starter unit transfer indicate that rapid loading of extension units onto the carrier domain facilitates efficient chain extension in a manner kinetically favorable to ultimate product formation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.