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Article ; Online: Engineering ribosomally synthesized and posttranslationally modified peptides as new antibiotics.

Vagstad, Anna L

2023 Volume 80, Page(s) 102891

Abstract: The rise of antimicrobial resistance is an urgent public health threat demanding the invention of new drugs to combat infections. Naturally sourced nonribosomal peptides (NRPs) have a long history as antimicrobial drugs. Through recent advances in genome ...

Abstract	The rise of antimicrobial resistance is an urgent public health threat demanding the invention of new drugs to combat infections. Naturally sourced nonribosomal peptides (NRPs) have a long history as antimicrobial drugs. Through recent advances in genome mining and engineering technologies, their ribosomally synthesized and posttranslationally modified peptide (RiPP) counterparts are poised to further contribute to the arsenal of anti-infectives. As natural products from diverse organisms involved in interspecies competition, many RiPPs already possess antimicrobial activities that can be further optimized as drug candidates. Owing to the mutability of precursor protein genes that encode their core structures and the availability of diverse posttranslational modification (PTM) enzymes with broad substrate tolerances, RiPP systems are well suited to engineer complex peptides with desired functions.
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Peptides/chemistry ; Protein Processing, Post-Translational ; Biological Products/metabolism
Chemical Substances	Anti-Bacterial Agents ; Peptides ; Biological Products
Language	English
Publishing date	2023-01-24
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1052045-4
ISSN	1879-0429 ; 0958-1669
ISSN (online)	1879-0429
ISSN	0958-1669
DOI	10.1016/j.copbio.2023.102891
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Article ; Online: Polyketide Trimming Shapes Dihydroxynaphthalene-Melanin and Anthraquinone Pigments.

Schmalhofer, Maximilian / Vagstad, Anna L / Zhou, Qiuqin / Bode, Helge B / Groll, Michael

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

2024 , Page(s) e2400184

Abstract: Pigments such as anthraquinones (AQs) and melanins are antioxidants, protectants, or virulence factors. AQs from the entomopathogenic bacterium Photorhabdus laumondii are produced by a modular type II polyketide synthase system. A key enzyme involved in ... ...

Abstract	Pigments such as anthraquinones (AQs) and melanins are antioxidants, protectants, or virulence factors. AQs from the entomopathogenic bacterium Photorhabdus laumondii are produced by a modular type II polyketide synthase system. A key enzyme involved in AQ biosynthesis is PlAntI, which catalyzes the hydrolysis of the bicyclic-intermediate-loaded acyl carrier protein, polyketide trimming, and assembly of the aromatic AQ scaffold. Here, multiple crystal structures of PlAntI in various conformations and with bound substrate surrogates or inhibitors are reported. Structure-based mutagenesis and activity assays provide experimental insights into the three sequential reaction steps to yield the natural product AQ-256. For comparison, a series of ligand-complex structures of two functionally related hydrolases involved in the biosynthesis of 1,8-dihydroxynaphthalene-melanin in pathogenic fungi is determined. These data provide fundamental insights into the mechanism of polyketide trimming that shapes pigments in pro- and eukaryotes.
Language	English
Publishing date	2024-03-16
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2808093-2
ISSN	2198-3844 ; 2198-3844
ISSN (online)	2198-3844
ISSN	2198-3844
DOI	10.1002/advs.202400184
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Article ; Online: Direct Detection of the α-Carbon Radical Intermediate Formed by OspD: Mechanistic Insights into Radical

Walls, William G / Vagstad, Anna L / Delridge, Tyler / Piel, Jörn / Broderick, William E / Broderick, Joan B

Journal of the American Chemical Society

2024 Volume 146, Issue 8, Page(s) 5550–5559

Abstract: OspD is a ... ...

Abstract	OspD is a radical
MeSH term(s)	S-Adenosylmethionine/chemistry ; Methionine ; Carbon ; Peptides/chemistry ; Amino Acids ; Racemethionine ; Valine
Chemical Substances	S-Adenosylmethionine (7LP2MPO46S) ; Methionine (AE28F7PNPL) ; Carbon (7440-44-0) ; Peptides ; Amino Acids ; Racemethionine (73JWT2K6T3) ; Valine (HG18B9YRS7)
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.3c13829
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Article ; Online: Emulating nonribosomal peptides with ribosomal biosynthetic strategies.

Mordhorst, Silja / Ruijne, Fleur / Vagstad, Anna L / Kuipers, Oscar P / Piel, Jörn

RSC chemical biology

2022 Volume 4, Issue 1, Page(s) 7–36

Abstract: Peptide natural products are important lead structures for human drugs and many nonribosomal peptides possess antibiotic activity. This makes them interesting targets for engineering approaches to generate peptide analogues with, for example, increased ... ...

Abstract	Peptide natural products are important lead structures for human drugs and many nonribosomal peptides possess antibiotic activity. This makes them interesting targets for engineering approaches to generate peptide analogues with, for example, increased bioactivities. Nonribosomal peptides are produced by huge mega-enzyme complexes in an assembly-line like manner, and hence, these biosynthetic pathways are challenging to engineer. In the past decade, more and more structural features thought to be unique to nonribosomal peptides were found in ribosomally synthesised and posttranslationally modified peptides as well. These streamlined ribosomal pathways with modifying enzymes that are often promiscuous and with gene-encoded precursor proteins that can be modified easily, offer several advantages to produce designer peptides. This review aims to provide an overview of recent progress in this emerging research area by comparing structural features common to both nonribosomal and ribosomally synthesised and posttranslationally modified peptides in the first part and highlighting synthetic biology strategies for emulating nonribosomal peptides by ribosomal pathway engineering in the second part.
Language	English
Publishing date	2022-12-06
Publishing country	England
Document type	Journal Article ; Review
ISSN	2633-0679
ISSN (online)	2633-0679
DOI	10.1039/d2cb00169a
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Article ; Online: Structural and Biochemical Insights into Post-Translational Arginine-to-Ornithine Peptide Modifications by an Atypical Arginase.

Mordhorst, Silja / Badmann, Thomas / Bösch, Nina M / Morinaka, Brandon I / Rauch, Hartmut / Piel, Jörn / Groll, Michael / Vagstad, Anna L

ACS chemical biology

2023 Volume 18, Issue 3, Page(s) 528–536

Abstract: Landornamide A is a ribosomally synthesized and post-translationally modified peptide (RiPP) natural product with antiviral activity. Its biosynthetic gene cluster encodes─among other maturases─the peptide arginase OspR, which converts arginine to ... ...

Abstract	Landornamide A is a ribosomally synthesized and post-translationally modified peptide (RiPP) natural product with antiviral activity. Its biosynthetic gene cluster encodes─among other maturases─the peptide arginase OspR, which converts arginine to ornithine units in an unusual post-translational modification. Peptide arginases are a recently discovered RiPP maturase family with few characterized representatives. They show little sequence similarity to conventional arginases, a well-characterized enzyme family catalyzing the hydrolysis of free arginine to ornithine and urea. Peptide arginases are highly promiscuous and accept a variety of substrate sequences. The molecular basis for binding the large peptide substrate and for the high promiscuity of peptide arginases remains unclear. Here, we report the first crystal structure of a peptide arginase at a resolution of 2.6 Å. The three-dimensional structure reveals common features and differences between conventional arginases and the peptide arginase: the binuclear metal cluster and the active-site environment strongly resemble each other, while the quaternary structures diverge. Kinetic analyses of OspR with various substrates provide new insights into the order of biosynthetic reactions during the post-translational maturation of landornamide A. These results provide the basis for pathway engineering to generate derivatives of landornamide A and for the general application of peptide arginases as biosynthetic tools for peptide engineering.
MeSH term(s)	Arginase/metabolism ; Arginine/metabolism ; Ornithine/metabolism ; Peptides/metabolism ; Protein Processing, Post-Translational
Chemical Substances	Arginase (EC 3.5.3.1) ; Arginine (94ZLA3W45F) ; Ornithine (E524N2IXA3) ; Peptides
Language	English
Publishing date	2023-02-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.2c00879
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Article ; Online: Posttranslationally Acting Arginases Provide a Ribosomal Route to Non-proteinogenic Ornithine Residues in Diverse Peptide Sequences.

Mordhorst, Silja / Morinaka, Brandon I / Vagstad, Anna L / Piel, Jörn

Angewandte Chemie (International ed. in English)

2020 Volume 59, Issue 48, Page(s) 21442–21447

Abstract: Ornithine is a component of many bioactive nonribosomal peptides but is challenging to incorporate into ribosomal products. We recently identified OspR, a cyanobacterial arginase-like enzyme that installs ornithines in the antiviral ribosomally ... ...

Abstract	Ornithine is a component of many bioactive nonribosomal peptides but is challenging to incorporate into ribosomal products. We recently identified OspR, a cyanobacterial arginase-like enzyme that installs ornithines in the antiviral ribosomally synthesised and posttranslationally modified peptide (RiPP) landornamide A. Here we report that OspR belongs to a larger family of peptide arginases from diverse organisms and RiPP types. In E. coli, seven selected enzymes converted arginine into ornithine with little preference for the leader type. A broad range of peptide sequences was modified, including polyarginine repeats. We also generated analogues of ornithine-containing nonribosomal peptides using RiPP technology. Five pseudo-nonribosomal products with ornithines at the correct positions were obtained, including a brevicidine analogue containing ornithine and a d-amino acid installed by the peptide epimerase OspD. These results suggest new opportunities for peptide bioengineering.
MeSH term(s)	Amino Acid Sequence ; Arginase/chemistry ; Arginase/metabolism ; Cyanobacteria/enzymology ; Molecular Conformation ; Ornithine/chemistry ; Ornithine/metabolism ; Peptides/chemistry ; Peptides/metabolism ; Protein Processing, Post-Translational ; Ribosomes/chemistry ; Ribosomes/metabolism
Chemical Substances	Peptides ; Ornithine (E524N2IXA3) ; Arginase (EC 3.5.3.1)
Language	English
Publishing date	2020-09-17
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202008990
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Article ; Online: Radical S-Adenosylmethionine Peptide Epimerases: Detection of Activity and Characterization of d-Amino Acid Products.

Morinaka, Brandon I / Vagstad, Anna L / Piel, Jörn

Methods in enzymology

2018 Volume 604, Page(s) 237–257

Abstract: The identification of the polytheonamide (poy) gene cluster led to the discovery of the enzyme PoyD, a member of the radical S-adenosylmethionine superfamily capable of introducing d-amino acids into a ribosomally synthesized peptide. This enzyme was ... ...

Abstract	The identification of the polytheonamide (poy) gene cluster led to the discovery of the enzyme PoyD, a member of the radical S-adenosylmethionine superfamily capable of introducing d-amino acids into a ribosomally synthesized peptide. This enzyme was used as a starting point to identify additional radical S-adenosylmethionine peptide epimerases in other cyanobacterial genomes, which show different epimerization patterns compared to PoyD. During the course of studying these enzymes by heterologous expression in Escherichia coli, we developed a two-step strategy to (1) detect epimerase activity and (2) localize where epimerization occurs based on an in vivo deuterium labeling strategy. The procedures for these two methods are described in the following chapter and will set the stage for further study of these enzymes.
MeSH term(s)	Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Biochemistry/methods ; Cloning, Molecular ; Cyanobacteria/genetics ; Cyanobacteria/metabolism ; Multigene Family ; Peptides/chemistry ; Peptides/metabolism ; Racemases and Epimerases/genetics ; Racemases and Epimerases/metabolism ; S-Adenosylmethionine/metabolism
Chemical Substances	Bacterial Proteins ; Peptides ; S-Adenosylmethionine (7LP2MPO46S) ; Racemases and Epimerases (EC 5.1.-)
Language	English
Publishing date	2018-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1557-7988 ; 0076-6879
ISSN (online)	1557-7988
ISSN	0076-6879
DOI	10.1016/bs.mie.2018.01.033
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Article ; Online: Ribosomally derived lipopeptides containing distinct fatty acyl moieties.

Hubrich, Florian / Bösch, Nina M / Chepkirui, Clara / Morinaka, Brandon I / Rust, Michael / Gugger, Muriel / Robinson, Serina L / Vagstad, Anna L / Piel, Jörn

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 3

Abstract: Lipopeptides represent a large group of microbial natural products that include important antibacterial and antifungal drugs and some of the most-powerful known biosurfactants. The vast majority of lipopeptides comprise cyclic peptide backbones N- ... ...

Abstract	Lipopeptides represent a large group of microbial natural products that include important antibacterial and antifungal drugs and some of the most-powerful known biosurfactants. The vast majority of lipopeptides comprise cyclic peptide backbones N-terminally equipped with various fatty acyl moieties. The known compounds of this type are biosynthesized by nonribosomal peptide synthetases, giant enzyme complexes that assemble their products in a non-gene-encoded manner. Here, we report the genome-guided discovery of ribosomally derived, fatty-acylated lipopeptides, termed selidamides. Heterologous reconstitution of three pathways, two from cyanobacteria and one from an arctic, ocean-derived alphaproteobacterium, allowed structural characterization of the probable natural products and suggest that selidamides are widespread over various bacterial phyla. The identified representatives feature cyclic peptide moieties and fatty acyl units attached to (hydroxy)ornithine or lysine side chains by maturases of the GCN5-related
MeSH term(s)	Anti-Bacterial Agents/metabolism ; Antifungal Agents/metabolism ; Biosynthetic Pathways ; Cyanobacteria/metabolism ; Lipopeptides/biosynthesis ; Lipopeptides/chemistry ; Peptide Synthases/metabolism ; Peptides, Cyclic ; Ribosomes/metabolism
Chemical Substances	Anti-Bacterial Agents ; Antifungal Agents ; Lipopeptides ; Peptides, Cyclic ; Peptide Synthases (EC 6.3.2.-) ; non-ribosomal peptide synthase (EC 6.3.2.-)
Language	English
Publishing date	2022-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2113120119
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Article ; Online: Polytheonamide biosynthesis showcasing the metabolic potential of sponge-associated uncultivated 'Entotheonella' bacteria.

Freeman, Michael F / Vagstad, Anna L / Piel, Jörn

Current opinion in chemical biology

2016 Volume 31, Page(s) 8–14

Abstract: The vast majority of microorganisms on the planet have not been grown under laboratory conditions due to unknown metabolic and environmental constraints. This uncultivated majority has enormous potential as a reservoir of unique enzymology and ... ...

Abstract	The vast majority of microorganisms on the planet have not been grown under laboratory conditions due to unknown metabolic and environmental constraints. This uncultivated majority has enormous potential as a reservoir of unique enzymology and biosynthetic pathways. The following review offers a glimpse into this unexplored enzymatic stockpile through recent progress made on the biosynthesis of the potent polytheonamide cytotoxins. These structurally highly complex pore-forming peptides, isolated from the marine sponge Theonella swinhoei, are synthesized by the ribosome and then modified through numerous unusual transformations including iterative epimerase and N-methyltransferase activities. The bacterial source of these metabolites was identified as the taxonomically remote, uncultivated sponge symbiont 'Entotheonella factor' with a biosynthetic prowess that rivals those of industrially exploited microorganisms.
MeSH term(s)	Animals ; Bacteria/metabolism ; Protein Biosynthesis ; Theonella/metabolism ; Theonella/microbiology
Language	English
Publishing date	2016-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1439176-4
ISSN	1879-0402 ; 1367-5931
ISSN (online)	1879-0402
ISSN	1367-5931
DOI	10.1016/j.cbpa.2015.11.002
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Zs.A 4986: Show issues

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Article ; Online: Introduction of d-Amino Acids in Minimalistic Peptide Substrates by an S-Adenosyl-l-Methionine Radical Epimerase.

Vagstad, Anna L / Kuranaga, Takefumi / Püntener, Salome / Pattabiraman, Vijaya R / Bode, Jeffrey W / Piel, Jörn

Angewandte Chemie (International ed. in English)

2019 Volume 58, Issue 8, Page(s) 2246–2250

Abstract: Post-translational modifying enzymes from the S-adenosyl-l-methionine (AdoMet) radical superfamily garner attention due to their ability to accomplish challenging biochemical reactions. Among them, a family of AdoMet radical epimerases catalyze ... ...

Abstract	Post-translational modifying enzymes from the S-adenosyl-l-methionine (AdoMet) radical superfamily garner attention due to their ability to accomplish challenging biochemical reactions. Among them, a family of AdoMet radical epimerases catalyze irreversible l- to d-amino acid transformations of diverse residues, including 18 sites in the complex sponge-derived polytheonamide toxins. Herein, the in vitro activity of the model epimerase OspD is reported and its catalytic mechanism and substrate flexibility is investigated. The wild-type enzyme was capable of leader-independent epimerization of not only the stand-alone core peptide, but also truncated and cyclic core variants. Introduction of d-amino acids can drastically alter the stability, structure, and activity of peptides; thus, epimerases offer opportunities in peptide bioengineering.
MeSH term(s)	Amino Acids/chemistry ; Amino Acids/metabolism ; Free Radicals/chemistry ; Free Radicals/metabolism ; Molecular Conformation ; Peptides/chemistry ; Peptides/metabolism ; Protein Processing, Post-Translational ; Racemases and Epimerases/chemistry ; Racemases and Epimerases/metabolism ; S-Adenosylmethionine/chemistry ; S-Adenosylmethionine/metabolism
Chemical Substances	Amino Acids ; Free Radicals ; Peptides ; S-Adenosylmethionine (7LP2MPO46S) ; Racemases and Epimerases (EC 5.1.-)
Language	English
Publishing date	2019-01-25
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.201809508
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