Curiouser and curiouser: progress in understanding the programming of iterative highly-reducing polyketide synthases

Cox, Russell J.

doi:10.1039/d2np00007e

Cited by 33 publications

(29 citation statements)

References 76 publications

(117 reference statements)

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“…52,160 HRPKS programming will not be elaborated further here, and the readers can refer to the excellent review by Cox that is also in this volume. 161 In this section, we will discuss recent representative case studies of how identication of shunt products has impacted the biosynthetic mining and investigation of fungal natural products.…”

Section: Shunt Product Formation During Heterologous Reconstitutionmentioning

confidence: 99%

Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining

Chiang¹,

Ohashi²,

Tang³

2023

Nat. Prod. Rep.

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Section: Shunt Product Formation During Heterologous Reconstitutionmentioning

confidence: 99%

Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining

Chiang¹,

Ohashi²,

Tang³

2023

Nat. Prod. Rep.

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“…1)-required for extension of the module 7 intermediate followed by oxazoline formation, suggesting that these domains kinetically and/or sterically outcompete the cassette enzymes, albeit imperfectly. It may be noteworthy that kinetic arguments are now also used to explain complex programming in iterative PKSs 41 and NRPS systems with trans-acting components 42 . Given that a high proportion of trans-AT PKSs systems comprise transacting enzymes including but not limited to β-branching cassettes 5,7 , it is likely that the existence of multiple control mechanisms is not limited to the virginiamycin system.…”

Section: Discussionmentioning

confidence: 99%

Decrypting the programming of β-methylation in virginiamycin M biosynthesis

et al. 2023

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During biosynthesis by multi-modular trans-AT polyketide synthases, polyketide structural space can be expanded by conversion of initially-formed electrophilic β-ketones into β-alkyl groups. These multi-step transformations are catalysed by 3-hydroxy-3-methylgluratryl synthase cassettes of enzymes. While mechanistic aspects of these reactions have been delineated, little information is available concerning how the cassettes select the specific polyketide intermediate(s) to target. Here we use integrative structural biology to identify the basis for substrate choice in module 5 of the virginiamycin M trans-AT polyketide synthase. Additionally, we show in vitro that module 7, at minimum, is a potential additional site for β-methylation. Indeed, analysis by HPLC-MS coupled with isotopic labelling and pathway inactivation identifies a metabolite bearing a second β-methyl at the expected position. Collectively, our results demonstrate that several control mechanisms acting in concert underpin β-branching programming. Furthermore, variations in this control – whether natural or by design – open up avenues for diversifying polyketide structures towards high-value derivatives.

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“…However, among the 43 PKS-NRPS hybrid BGCs recovered across all samples, none encoded the predicted enzymes. Interestingly, highly-reducing PKSs domains are traditionally of fungal origin [44], while the amino acid statine is primarily associated with bacteria [45]. Given the possibility that a low abundant organism (thus, not assembled) could account for production, we extracted all KS domains from the unassembled reads along with experimentally characterized fungal highly reducing [46][47][48] and statine-related KS domains (i.e., didemnin B and burkholdac A) from published literature [27,49], and characterized them with NaPDoS2 [50].…”

Section: Metagenomic Analysesmentioning

confidence: 99%

Small Moleculein situResin Capture – A Compound First Approach to Natural Product Discovery

Bogdanov

Salib

Chase

et al. 2023

Preprint

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Microbial natural products remain a crucial source of lead compounds for drug discovery. Yet, commonly employed discovery techniques are plagued by the rediscovery of known compounds, a narrow taxonomic focus on the relatively few microbes that can be cultured, and laboratory growth conditions that do not support biosynthetic gene expression. Here we exploit a culture independent approach to microbial natural product discovery that we call the Small Molecule in situ Resin Capture (SMIRC) technique. SMIRC represents a new approach to mine natural products from underexplored ‘chemical space’. We demonstrate the application of this approach with the discovery of numerous new compounds including cabrillospiral, which possesses a new carbon skeleton with a functional group not previously observed among natural products. In contrast to traditional culture-based methods, this compound first approach can capture structurally complex small molecules across all domains of life in a single deployment while relying on Nature to provide the complex and poorly understood environmental cues needed to elicit biosynthetic gene expression. We target marine habitats given the potential for chemical novelty, yet the SMIRC method is applicable across other environments. We demonstrate that SMIRC recovers novel compounds with sufficient yields for NMR-based structure assignment and employ a variety of approaches including expanded deployments, in situ cultivation, and metagenomics to address compound re-supply. This approach has the potential to provide unprecedented access to new natural product chemotypes with broad implications for drug discovery.

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Curiouser and curiouser: progress in understanding the programming of iterative highly-reducing polyketide synthases

Abstract: Current understanding of iterative highly programmed Type 1 PKS that control starter unit selection, chain length, methylation pattern, and stereochemistry.

Cited by 33 publications

References 76 publications

Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining

Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining

Decrypting the programming of β-methylation in virginiamycin M biosynthesis

Small Moleculein situResin Capture – A Compound First Approach to Natural Product Discovery

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