Computer-aided re-engineering of nonribosomal peptide and polyketide biosynthetic assembly lines

Alanjary, Mohammad; Cano-Prieto, Carolina; Gross, Harald; Medema, Marnix H.

doi:10.1039/c9np00021f

Cited by 38 publications

(36 citation statements)

References 138 publications

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“…[16] Future genomic and molecular biological studies on Pseudoxylaria are now directed at elucidating and engineering their biosynthetic origin. [17] Encouraged by the identified structural diversity of tetrapeptides, we set out to isolate the two major metabolites identified from the second MS 2 subnetwork ( Figure 1D) and TIC, which were dominantly detectable within the 60 % MeOH SPE fractions of culture extracts (Supporting Information). Again, MS-guided purification led to the isolation of analytically pure compound 5, which was assigned the molecular formula C 22 H 30 O 5 N 2 and nine degrees of unsaturation based on the ESI-HRMS mass spectrum (HRMS (ESI) m/z [M + H] + calcd.…”

Section: Resultsmentioning

confidence: 99%

Targeted Discovery of Tetrapeptides and Cyclic Polyketide‐Peptide Hybrids from a Fungal Antagonist of Farming Termites

Schalk

Guo

et al. 2020

ChemBioChem

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Dedicated to Prof. Rolf Huisgen. Herein, we report the targeted isolation and characterization of four linear nonribosomally synthesized tetrapeptides (pseudoxylaramide AD) and two cyclic nonribosomal peptide synthetase-polyketide synthase-derived natural products (xylacremolide A and B) from the termite-associated stowaway fungus Pseudoxylaria sp. X187. The fungal strain was prioritized for further metabolic analysis based on its taxonomical position and morphological and bioassay data. Metabolic data were dereplicated based on high-resolution tandem mass spectrometry data and global molecular networking analysis. The structure of all six new natural products was elucidated based on a combination of 1D and 2D NMR analysis, Marfey's analysis and X-ray crystallography.

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Section: Resultsmentioning

confidence: 99%

Targeted Discovery of Tetrapeptides and Cyclic Polyketide‐Peptide Hybrids from a Fungal Antagonist of Farming Termites

Schalk

Guo

et al. 2020

ChemBioChem

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“…Early attempts for the engineering of PKSs and NRPSs were conducted via precursor directed biosynthesis (PDB) and mutasynthesis (Alanjary et al, 2019) (Table 1). PDB is a strategy of creating a new product by providing an external substrate instead of the native substrate of the recognition domain (AT and A domain).…”

Section: Substrate Exchangementioning

confidence: 99%

“…Despite these limitations, mutasynthesis is still useful when applied together with domain and module engineering in a synergistic manner. For example, non-natural precursors generated by semisynthetic or click chemistry could be fed, accompanied by the deletion of the native precursor biosynthetic genes and the mutations of PKS or NRPS enzymes to attach the pharmacophore-containing moiety or dye for novel chemical production (Alanjary et al, 2019).…”

Section: Substrate Exchangementioning

confidence: 99%

“…Likewise, NRPS comprises numerous modules, with each of them responsible for the incorporation and modification of one amino acid substrate to extend the polypeptide product, such as daptomycin (antibiotic), actinomycin D (antitumor), cyclosporine A (immunosuppressant), and other potential clinical agents (Walsh, 2016;Sussmuth and Mainz, 2017). As the organization and the order of these modules are co-linearly correlated with each unit of the final polyketide and polypeptide products, the target modules of rational engineering could be predicted for the production of novel derivatives having the modified unit at a specific position (Alanjary et al, 2019). Using this modular biosynthetic logic of type I modular PKS and NRPS, each reaction of a module was capable of being separated from the original assembly reactions and repurposed to construct de novo biosynthetic pathway for other chemicals (Pang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis

Hwang

Lee

Cho

et al. 2020

Front. Mol. Biosci.

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In nature, various enzymes govern diverse biochemical reactions through their specific three-dimensional structures, which have been harnessed to produce many useful bioactive compounds including clinical agents and commodity chemicals. Polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are particularly unique multifunctional enzymes that display modular organization. Individual modules incorporate their own specific substrates and collaborate to assemble complex polyketides or non-ribosomal polypeptides in a linear fashion. Due to the modular properties of PKSs and NRPSs, they have been attractive rational engineering targets for novel chemical production through the predictable modification of each moiety of the complex chemical through engineering of the cognate module. Thus, individual reactions of each module could be separated as a retro-biosynthetic biopart and repurposed to new biosynthetic pathways for the production of biofuels or commodity chemicals. Despite these potentials, repurposing attempts have often failed owing to impaired catalytic activity or the production of unintended products due to incompatible protein-protein interactions between the modules and structural perturbation of the enzyme. Recent advances in the structural, computational, and synthetic tools provide more opportunities for successful repurposing. In this review, we focused on the representative strategies and examples for the repurposing of modular PKSs and NRPSs, along with their advantages and current limitations. Thereafter, synthetic biology tools and perspectives were suggested for potential further advancement, including the rational and large-scale high-throughput approaches. Ultimately, the potential diverse reactions from modular PKSs and NRPSs would be leveraged to expand the reservoir of useful chemicals.

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“…Today, technological 63 and methodological advances allow to establish more precise views of the chemo-biologic aspects of 64 life. In the field of NPs, advances in genomics and metagenomics now allow the anticipation of the 65 chemical output directly from environmental DNA (Alanjary et al, 2019;Craig et al, 2009). 66 Developments in metabolite profiling by mass spectrometry (MS) grant access to large volumes of 67 high-quality spectral data from minimal amount of samples and appropriate data analysis workflows 68 allow to efficiently mine such data (Wolfender et al, 2019).…”

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confidence: 99%

Taxonomically informed scoring enhances confidence in natural products annotation

Rutz

Dounoue-Kubo

Ollivier

et al. 2019

Preprint

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25 Mass spectrometry (MS) hyphenated to liquid chromatography (LC)-MS offers unrivalled sensitivity 26 for metabolite profiling of complex biological matrices encountered in natural products (NP) research. 27 With advanced platforms LC, MS/MS spectra are acquired in an untargeted manner on most detected 28 features. This generates massive and complex sets of spectral data that provide valuable structural 29 information on most analytes. To interpret such datasets, computational methods are mandatory. To 30 this extent, computerized annotation of metabolites links spectral data to candidate structures. When 31 profiling complex extracts spectra are often organized in clusters by similarity via Molecular 32 Networking (MN). A spectral matching score is usually established between the acquired data and 33 experimental or theoretical spectral databases (DB). The process leads to various candidate structures 34 for each MS features. At this stage, obtaining high annotation confidence level remains a challenge 35 notably due to the high chemodiversity of specialized metabolomes. 36

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Computer-aided re-engineering of nonribosomal peptide and polyketide biosynthetic assembly lines

Abstract: This review highlights recent advancements in engineering biosynthetic assembly lines and new computational tools that aid in parts search, assembly line engineering, and refinement.

Cited by 38 publications

References 138 publications

Targeted Discovery of Tetrapeptides and Cyclic Polyketide‐Peptide Hybrids from a Fungal Antagonist of Farming Termites

Targeted Discovery of Tetrapeptides and Cyclic Polyketide‐Peptide Hybrids from a Fungal Antagonist of Farming Termites

Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis

Taxonomically informed scoring enhances confidence in natural products annotation

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