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  1. Article: Genome Mining for New Enzyme Chemistry.

    Nguyen, Dinh T / Mitchell, Douglas A / van der Donk, Wilfred A

    ACS catalysis

    2024  Volume 14, Issue 7, Page(s) 4536–4553

    Abstract: A revolution in the field of biocatalysis has enabled scalable access to compounds of high societal values using enzymes. The construction of biocatalytic routes relies on the reservoir of available enzymatic transformations. A review of uncharacterized ... ...

    Abstract A revolution in the field of biocatalysis has enabled scalable access to compounds of high societal values using enzymes. The construction of biocatalytic routes relies on the reservoir of available enzymatic transformations. A review of uncharacterized proteins predicted from genomic sequencing projects shows that a treasure trove of enzyme chemistry awaits to be uncovered. This Review highlights enzymatic transformations discovered through various genome mining methods and showcases their potential future applications in biocatalysis.
    Language English
    Publishing date 2024-03-12
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2155-5435
    ISSN 2155-5435
    DOI 10.1021/acscatal.3c06322
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: PEARL-catalyzed peptide bond formation after chain reversal during the biosynthesis of non-ribosomal peptides.

    Yu, Yue / van der Donk, Wilfred A

    bioRxiv : the preprint server for biology

    2023  

    Abstract: A subset of nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are encoded in their biosynthetic gene clusters (BGCs) with enzymes annotated as lantibiotic dehydratases. The functions of these putative lantibiotic dehydratases ... ...

    Abstract A subset of nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are encoded in their biosynthetic gene clusters (BGCs) with enzymes annotated as lantibiotic dehydratases. The functions of these putative lantibiotic dehydratases remain unknown. Here, we characterize an NRPS-PKS BGC with a putative lantibiotic dehydratase from the bacterium
    Language English
    Publishing date 2023-12-23
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.23.573212
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Unexpected transformations during pyrroloiminoquinone biosynthesis.

    Figueroa, Josseline Ramos / Zhu, Lingyang / van der Donk, Wilfred A

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Pyrroloiminoquinone containing natural products have long been known for their biological activities. They are derived from tryptophan, but their biosynthetic pathways have remained elusive. Studies on the biosynthetic gene cluster (BGC) that produces ... ...

    Abstract Pyrroloiminoquinone containing natural products have long been known for their biological activities. They are derived from tryptophan, but their biosynthetic pathways have remained elusive. Studies on the biosynthetic gene cluster (BGC) that produces the ammosamides revealed that the first step is attachment of Trp to the C-terminus of a scaffold peptide in an ATP and tRNA dependent manner catalyzed by a PEptide Amino-acyl tRNA ligase (PEARL). The indole of the Trp is then oxidized to a hydroxyquinone. We previously proposed a chemically plausible and streamlined pathway for converting this intermediate to the ammosamides using additional enzymes encoded in the BGC. In this study, we report the activity of four additional enzymes that show that the proposed pathway is incorrect and that Nature's route towards pyrroloiminoquinones is much more complicated. We demonstrate that, surprisingly, the amino groups in pyrroloiminoquinones are derived from three different sources, glycine, asparagine, and leucine, all introduced in a tRNA dependent manner. We also show that an FAD-dependent putative glycine oxidase is required for the process that incorporates the nitrogens from glycine and leucine, and that a quinone reductase is required for the incorporation of the asparagine. Additionally, we provide the first insights into the evolutionary origin of the PEARLs as well as related enzymes such as the glutamyl-tRNA dependent dehydratases involved in the biosynthesis of lanthipeptides and thiopeptides. These enzymes appear to all have descended from the ATP-GRASP protein family.
    Language English
    Publishing date 2024-03-14
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.03.12.584671
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  4. Article ; Online: syn

    Sarksian, Raymond / Zhu, Lingyang / van der Donk, Wilfred A

    Chemical communications (Cambridge, England)

    2023  Volume 59, Issue 9, Page(s) 1165–1168

    Abstract: Methyllanthionine (MeLan) containing macrocycles are key structural features of lanthipeptides. They are formed typically ... ...

    Abstract Methyllanthionine (MeLan) containing macrocycles are key structural features of lanthipeptides. They are formed typically by
    MeSH term(s) Threonine ; Cysteine ; Protein Processing, Post-Translational ; Cyclization
    Chemical Substances Threonine (2ZD004190S) ; Cysteine (K848JZ4886)
    Language English
    Publishing date 2023-01-26
    Publishing country England
    Document type Journal Article
    ZDB-ID 1472881-3
    ISSN 1364-548X ; 1359-7345 ; 0009-241X
    ISSN (online) 1364-548X
    ISSN 1359-7345 ; 0009-241X
    DOI 10.1039/d2cc06345j
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Proteases Involved in Leader Peptide Removal during RiPP Biosynthesis.

    Eslami, Sara M / van der Donk, Wilfred A

    ACS bio & med chem Au

    2023  Volume 4, Issue 1, Page(s) 20–36

    Abstract: Ribosomally synthesized and post-translationally modified peptides (RiPPs) have received much attention in recent years because of their promising bioactivities and the portability of their biosynthetic pathways. Heterologous expression studies of RiPP ... ...

    Abstract Ribosomally synthesized and post-translationally modified peptides (RiPPs) have received much attention in recent years because of their promising bioactivities and the portability of their biosynthetic pathways. Heterologous expression studies of RiPP biosynthetic enzymes identified by genome mining often leave a leader peptide on the final product to prevent toxicity to the host and to allow the attachment of a genetically encoded affinity purification tag. Removal of the leader peptide to produce the mature natural product is then carried out in vitro with either a commercial protease or a protease that fulfills this task in the producing organism. This review covers the advances in characterizing these latter cognate proteases from bacterial RiPPs and their utility as sequence-dependent proteases. The strategies employed for leader peptide removal have been shown to be remarkably diverse. They include one-step removal by a single protease, two-step removal by two dedicated proteases, and endoproteinase activity followed by aminopeptidase activity by the same protease. Similarly, the localization of the proteolytic step varies from cytoplasmic cleavage to leader peptide removal during secretion to extracellular leader peptide removal. Finally, substrate recognition ranges from highly sequence specific with respect to the leader and/or modified core peptide to nonsequence specific mechanisms.
    Language English
    Publishing date 2023-12-13
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2694-2437
    ISSN (online) 2694-2437
    DOI 10.1021/acsbiomedchemau.3c00059
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Expression of Lanthipeptides in Human Cells.

    Eslami, Sara M / Rahman, Imran R / van der Donk, Wilfred A

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Cyclic peptides represent a burgeoning area of interest in therapeutic and biotechnological research. In opposition to their linear counterparts, cyclic peptides, such as certain ribosomally synthesized and post-translationally modified peptides (RiPPs), ...

    Abstract Cyclic peptides represent a burgeoning area of interest in therapeutic and biotechnological research. In opposition to their linear counterparts, cyclic peptides, such as certain ribosomally synthesized and post-translationally modified peptides (RiPPs), are more conformationally constrained and less susceptible to proteolytic degradation. The lanthipeptide RiPP cytolysin L forms a covalently enforced helical structure that may be used to disrupt helical interactions at protein-protein interfaces. Herein, an expression system is reported to produce lanthipeptides and structurally diverse cytolysin L derivatives in mammalian cells. Successful targeting of lanthipeptides to the nucleus is demonstrated. In vivo expression and targeting of such peptides in mammalian cells may allow for screening of lanthipeptide inhibitors of native protein-protein interactions.
    Language English
    Publishing date 2023-10-23
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.19.563208
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Facile Method for Determining Lanthipeptide Stereochemistry.

    Luo, Youran / Xu, Shuyun / Frerk, Autumn M / van der Donk, Wilfred A

    Analytical chemistry

    2024  Volume 96, Issue 4, Page(s) 1767–1773

    Abstract: Lanthipeptides make up a large group of natural products that belong to the ribosomally synthesized and post-translationally modified peptides (RiPPs). Lanthipeptides contain lanthionine and methyllanthionine bis-amino acids that have varying ... ...

    Abstract Lanthipeptides make up a large group of natural products that belong to the ribosomally synthesized and post-translationally modified peptides (RiPPs). Lanthipeptides contain lanthionine and methyllanthionine bis-amino acids that have varying stereochemistry. The stereochemistry of new lanthipeptides is often not determined because current methods require equipment that is not standard in most laboratories. In this study, we developed a facile, efficient, and user-friendly method for detecting lanthipeptide stereochemistry, utilizing advanced Marfey's analysis with detection by liquid chromatography coupled with mass spectrometry (LC-MS). Under optimized conditions, 0.05 mg of peptide is sufficient to characterize the stereochemistry of five (methyl)lanthionines of different stereochemistry using a simple liquid chromatography setup, which is a much lower detection limit than current methods. In addition, we describe methods to readily access standards of the three different methyllanthionine stereoisomers and two different lanthionine stereoisomers that have been reported in known lanthipeptides. The developed workflow uses a commonly used nonchiral column system and offers a scalable platform to assist antimicrobial discovery. We illustrate its utility with an example of a lanthipeptide discovered by genome mining.
    MeSH term(s) Peptides/chemistry ; Sulfides/chemistry ; Alanine/chemistry ; Chromatography, Liquid
    Chemical Substances lanthionine (JO78O46X3K) ; Peptides ; Sulfides ; Alanine (OF5P57N2ZX)
    Language English
    Publishing date 2024-01-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1508-8
    ISSN 1520-6882 ; 0003-2700
    ISSN (online) 1520-6882
    ISSN 0003-2700
    DOI 10.1021/acs.analchem.3c04958
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4033: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  8. Article ; Online: Divergent Evolution of Lanthipeptide Stereochemistry.

    Sarksian, Raymond / van der Donk, Wilfred A

    ACS chemical biology

    2022  Volume 17, Issue 9, Page(s) 2551–2558

    Abstract: The three-dimensional structure of natural products is critical for their biological activities and, as such, enzymes have evolved that specifically generate active stereoisomers. Lanthipeptides are post-translationally modified peptidic natural products ...

    Abstract The three-dimensional structure of natural products is critical for their biological activities and, as such, enzymes have evolved that specifically generate active stereoisomers. Lanthipeptides are post-translationally modified peptidic natural products that contain macrocyclic thioethers featuring lanthionine (Lan) and/or methyllanthionine (MeLan) residues with defined stereochemistry. In this report, we compare two class I lanthipeptide biosynthetic gene clusters (BGCs),
    MeSH term(s) Biological Products ; Hydro-Lyases ; Lyases ; Methyltransferases ; Peptides/chemistry ; Sulfides/chemistry
    Chemical Substances Biological Products ; Peptides ; Sulfides ; Methyltransferases (EC 2.1.1.-) ; Lyases (EC 4.-) ; Hydro-Lyases (EC 4.2.1.-)
    Language English
    Publishing date 2022-08-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.2c00492
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Improved production of class I lanthipeptides in

    Lee, Hyunji / Wu, Chunyu / Desormeaux, Emily K / Sarksian, Raymond / van der Donk, Wilfred A

    Chemical science

    2023  Volume 14, Issue 10, Page(s) 2537–2546

    Abstract: Lanthipeptides are ribosomally synthesised and post-translationally modified peptides containing lanthionine (Lan) and methyllanthionine (MeLan) residues that are formed by dehydration of Ser/Thr residues followed by conjugate addition of Cys to the ... ...

    Abstract Lanthipeptides are ribosomally synthesised and post-translationally modified peptides containing lanthionine (Lan) and methyllanthionine (MeLan) residues that are formed by dehydration of Ser/Thr residues followed by conjugate addition of Cys to the resulting dehydroamino acids. Class I lanthipeptide dehydratases utilize glutamyl-tRNA
    Language English
    Publishing date 2023-02-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2559110-1
    ISSN 2041-6539 ; 2041-6520
    ISSN (online) 2041-6539
    ISSN 2041-6520
    DOI 10.1039/d2sc06597e
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Substrate Specificity of the Flavoenzyme BhaC

    Daniels, Page N / van der Donk, Wilfred A

    Biochemistry

    2022  Volume 62, Issue 2, Page(s) 378–387

    Abstract: The preparation of protein-protein, protein-peptide, and protein-small molecule conjugates is important for a variety of applications, such as vaccine production, immunotherapies, preparation of antibody-drug conjugates, and targeted delivery of ... ...

    Abstract The preparation of protein-protein, protein-peptide, and protein-small molecule conjugates is important for a variety of applications, such as vaccine production, immunotherapies, preparation of antibody-drug conjugates, and targeted delivery of therapeutics. To achieve site-selective conjugation, selective chemical or enzymatic functionalization of proteins is required. We have recently reported biosynthetic pathways in which small, catalytic scaffold peptides are utilized for the generation of amino acid-derived natural products called pearlins. In these systems, peptide amino-acyl tRNA ligases (PEARLs) append amino acids to the C-terminus of a scaffold peptide, and tailoring enzymes encoded in the biosynthetic gene clusters modify the PEARL-appended amino acid to generate a variety of natural products. Herein, we investigate the substrate selectivity of one such tailoring enzyme, BhaC
    MeSH term(s) Substrate Specificity ; Peptides/chemistry ; Proteins ; Amino Acids ; Biological Products/metabolism
    Chemical Substances Peptides ; Proteins ; Amino Acids ; Biological Products
    Language English
    Publishing date 2022-05-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.2c00206
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 217: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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