Labelling studies in the biosynthesis of polyketides and non-ribosomal peptides

Hou, Anwei; Dickschat, Jeroen S.

doi:10.1039/d2np00071g

Cited by 7 publications

(7 citation statements)

References 179 publications

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“…To fully assign the carbon signals of the tetrayne moiety in 6 , P. protegens Cab57 was cultured with [U– 13 C]- d -glucose to enhance the 13 C concentration in the carbon chain of protegenin A ( 6 ) . However, when [U– 13 C]- d -glucose was used as the main carbon source instead of GlcNAc, , the production of protegenin A ( 6 ) by P.…”

Section: Resultsmentioning

confidence: 99%

“…To fully assign the carbon signals of the tetrayne moiety in 6, P. protegens Cab57 was cultured with [U− 13 C]-D-glucose to enhance the 13 C concentration in the carbon chain of protegenin A (6). 21 However, when [U− 13 C]-D-glucose was used as the main carbon source instead of GlcNAc, 9,22 the production of protegenin A (6) by P. protegens Cab57 drastically decreased, and the incorporation of the 13 C-label was inefficient. It was difficult for [ 13 C 6 ]-GlcNAc to obtain the quantity required to conduct the labeling experiment.…”

Section: Production Of Caryoynencins By the P Protegensmentioning

confidence: 99%

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Structures and Biosynthesis of Caryoynencins, Unstable Bacterial Polyynes from Pseudomonas protegens Recombinant Expressing the cayG Gene

Suenaga,

Katayama,

Kitamura

et al. 2023

J. Org. Chem.

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Bacteria in certain genera can produce "bacterial polyynes" that contain a conjugated C�C bond starting from a terminal alkyne. Protegenin A is a derivative of octadecanoic acid that contains an ene−tetrayne moiety. It was discovered in Pseudomonas protegens Cab57 and exhibits strong antioomycete and moderate antifungal activity. By introducing cayG, a cytochrome P450 gene from Burkholderia caryophylli, into P. protegens Cab57, protegenin A was converted into more complex polyynes, caryoynencins A−E. A purification method that minimized the degradation and isomerization of caryoynencins was established. For the first time, as far as we know, the 1 H and 13 C{ 1 H} NMR signals of caryoynencins were completely assigned by analyzing the NMR data of the isolated compounds and protegenin A enriched with [1-13 C]-or [2-13 C]-acetate. Through the structural analysis of caryoynencins D/E and bioconversion experiments, we observed that CayG constructs the allyl alcohol moiety of caryoynencins A−C through sequential hydroxylation, dehydration, and hydroxylation. The recombinant strain exhibited a stronger antioomycete activity compared to the wild-type strain. This paper proposes a stable purification and structural determination method for various bacterial polyynes, and P. protegens Cab57 holds promise as an engineering host for the production of biologically active polyynes.

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Section: Resultsmentioning

confidence: 99%

Section: Production Of Caryoynencins By the P Protegensmentioning

confidence: 99%

Structures and Biosynthesis of Caryoynencins, Unstable Bacterial Polyynes from Pseudomonas protegens Recombinant Expressing the cayG Gene

Suenaga,

Katayama,

Kitamura

et al. 2023

J. Org. Chem.

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“…Peptide labeling and stapling have attracted much attention as potential drug therapeutics and chemical probes. However, the anchoring sites for native peptide labeling and stapling are mainly dominated by reactive Cys and Lys. , The excellent functional group tolerance and synthetic robustness of our strategy for amide modification enable an attractive anchoring site to construct novel labeled peptides and stapled peptides.…”

Section: Resultsmentioning

confidence: 99%

“…Peptide Labeling and Stapling Studies. Peptide labeling 50 and stapling 51 have attracted much attention as potential drug therapeutics and chemical probes. However, the anchoring sites for native peptide labeling and stapling are mainly dominated by reactive Cys 52 and Lys.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Site-Selective Arylation of Carboxamides from Unprotected Peptides

Chen

et al. 2023

J. Am. Chem. Soc.

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The amidated peptides are an important class of biologically active compounds due to their unique biological properties and wide applications as potential peptide drugs and biomarkers. Despite the abundance of free amide motifs (Asn, Gln, and C-terminal amide) in native peptides, late-stage modification of the amide unit in naturally occurring peptides remains very rare because of the intrinsically weak nucleophilicity of amides and the interference of multiple competing nucleophilic residues, which generally lead to undesired side reactions. Herein, chemoselective arylation of amides in unprotected polypeptides has been developed under an air atmosphere to afford the N-aryl amide peptides bearing various functional motifs. Its success relies on the combination of gold catalysis and silver salt to differentiate the relative inert amide among a collection of reactive nucleophilic amino acid residues (e.g., −NH 2 , −OH, and −COOH), favoring the C−N bond coupling toward amides over other more nucleophilic groups. Experimental and DFT studies reveal a crucial role of the silver cation, which serves as a transient coordination mask of the more reactive reaction sites, overcoming the inherently low reactivity of amides. The excellent biocompatibility of this strategy has been applied to functionalize a wide range of peptide drugs and complex peptides. The application could be further extended to peptide labeling and peptide stapling.

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“…Stable isotopic labeling is a valuable technique for both primary and specialized metabolism research [1][2][3]. Using this approach, researchers can track the transformation and incorporation of isotopically substituted precursor metabolites in biological systems, which can provide mechanistic details about both catabolic and biosynthetic pathways.…”

Section: Introductionmentioning

confidence: 99%

Detection of inverse stable isotopic labeling in untargeted metabolomic data

Liebergesell,

Murdock,

Puri

2024

Preprint

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Stable isotopic labeling is a powerful tool for discovering natural products that incorporate precursors of interest and for determining the biosynthetic origin of metabolites. When isotopically substituted precursors are not available commercially or synthetically, inverse stable isotopic labeling (InverSIL) is a useful alternative. With InverSIL, an organism is grown on an isotopically substituted medium and then fed precursors of natural isotopic abundance which can be tracked by mass spectrometry, thereby bypassing issues with precursor availability. Currently, there is no automated way to identify precursor incorporation in untargeted metabolomic data using InverSIL without specifying an expected change in the mass-to-charge ratio of metabolites that have incorporated the precursor. This makes it difficult to identify unknown natural products that may incorporate portions of precursors of interest using new biochemistry, or to rapidly identify incorporation of multiple precursors into different metabolites simultaneously. To address this, we developed a new, robust workflow for the automated identification of inverse stable isotopic labeling in untargeted metabolomic data. We then use this method to identify metabolites that incorporate para-aminobenzoic acid and different portions of L-methionine, including in the same sample, and in the process discover the likely biosynthetic origin for the C-7 and C-9 methyl groups of the pterin portion of dephosphotetrahydromethanopterin; a C1 transfer coenzyme produced by methylotrophic bacteria. This workflow can be used in the future to streamline the use of the versatile InverSIL approach for natural product and metabolism research.

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Labelling studies in the biosynthesis of polyketides and non-ribosomal peptides

Abstract: This review summarises the recent studies on the biosynthesis of polyketides, non-ribosomal peptides and their hybrids using isotopic labelling experiments.

Cited by 7 publications

References 179 publications

Structures and Biosynthesis of Caryoynencins, Unstable Bacterial Polyynes from Pseudomonas protegens Recombinant Expressing the cayG Gene

Structures and Biosynthesis of Caryoynencins, Unstable Bacterial Polyynes from Pseudomonas protegens Recombinant Expressing the cayG Gene

Site-Selective Arylation of Carboxamides from Unprotected Peptides

Detection of inverse stable isotopic labeling in untargeted metabolomic data

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