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Article ; Online: Strategies to access biosynthetic novelty in bacterial genomes for drug discovery.

Hemmerling, Franziska / Piel, Jörn

2022 Volume 21, Issue 5, Page(s) 359–378

Abstract: Bacteria provide a rich source of natural products with potential therapeutic applications, such as novel antibiotic classes or anticancer drugs. Bioactivity-guided screening of bacterial extracts and characterization of biosynthetic pathways for drug ... ...

Abstract	Bacteria provide a rich source of natural products with potential therapeutic applications, such as novel antibiotic classes or anticancer drugs. Bioactivity-guided screening of bacterial extracts and characterization of biosynthetic pathways for drug discovery is now complemented by the availability of large (meta)genomic collections, placing researchers into the postgenomic, big-data era. The progress in next-generation sequencing and the rise of powerful computational tools provide unprecedented insights into unexplored taxa, ecological niches and 'biosynthetic dark matter', revealing diverse and chemically distinct natural products in previously unstudied bacteria. In this Review, we discuss such sources of new chemical entities and the implications for drug discovery with a particular focus on the strategies that have emerged in recent years to identify and access novelty.
MeSH term(s)	Bacteria/genetics ; Bacteria/metabolism ; Biological Products/chemistry ; Computational Biology ; Drug Discovery ; Genome, Bacterial ; Genomics ; Humans
Chemical Substances	Biological Products
Language	English
Publishing date	2022-03-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/s41573-022-00414-6
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Article ; Online: Site-specific bioorthogonal protein labelling by tetrazine ligation using endogenous β-amino acid dienophiles.

Richter, Daniel / Lakis, Edgars / Piel, Jörn

Nature chemistry

2023 Volume 15, Issue 10, Page(s) 1422–1430

Abstract: The tetrazine ligation is an inverse electron-demand Diels-Alder reaction widely used for bioorthogonal modifications due to its versatility, site specificity and fast reaction kinetics. A major limitation has been the incorporation of dienophiles in ... ...

Abstract	The tetrazine ligation is an inverse electron-demand Diels-Alder reaction widely used for bioorthogonal modifications due to its versatility, site specificity and fast reaction kinetics. A major limitation has been the incorporation of dienophiles in biomolecules and organisms, which relies on externally added reagents. Available methods require the incorporation of tetrazine-reactive groups by enzyme-mediated ligations or unnatural amino acid incorporation. Here we report a tetrazine ligation strategy, termed TyrEx (tyramine excision) cycloaddition, permitting autonomous dienophile generation in bacteria. It utilizes a unique aminopyruvate unit introduced by post-translational protein splicing at a short tag. Tetrazine conjugation occurs rapidly with a rate constant of 0.625 (15) M
Language	English
Publishing date	2023-07-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2464596-5
ISSN	1755-4349 ; 1755-4330
ISSN (online)	1755-4349
ISSN	1755-4330
DOI	10.1038/s41557-023-01252-8
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Article ; Online: Opening up the Single-Cell Toolbox for Microbial Natural Products Research.

Cahn, Jackson K B / Piel, Jörn

Angewandte Chemie (International ed. in English)

2021 Volume 60, Issue 34, Page(s) 18412–18428

Abstract: The diverse microbes that produce natural products represent an important source of novel therapeutics, drug leads, and scientific tools. However, the vast majority have not been grown in axenic culture and are members of complex communities. While meta-' ...

Abstract	The diverse microbes that produce natural products represent an important source of novel therapeutics, drug leads, and scientific tools. However, the vast majority have not been grown in axenic culture and are members of complex communities. While meta-'omic methods such as metagenomics, -transcriptomics, and -proteomics reveal collective molecular features of this "microbial dark matter", the study of individual microbiome members can be challenging. To address these limits, a number of techniques with single-bacterial resolution have been developed in the last decade and a half. While several of these are embraced by microbial ecologists, there has been less use by researchers interested in mining microbes for natural products. In this review, we discuss the available and emerging techniques for targeted single-cell analysis with a particular focus on applications to the discovery and study of natural products.
MeSH term(s)	Biological Products/analysis ; Microbiota ; Single-Cell Analysis
Chemical Substances	Biological Products
Language	English
Publishing date	2021-03-26
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.201900532
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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: In Vivo Production of Diverse β-Amino Acid-Containing Proteins.

Lakis, Edgars / Magyari, Sarolt / Piel, Jörn

Angewandte Chemie (International ed. in English)

2022 Volume 61, Issue 29, Page(s) e202202695

Abstract: The wide range of moieties installed in ribosomally synthesized and post-translationally modified peptides (RiPPs) suggests largely untapped potential for protein engineering. However, many RiPP maturases recognize target peptide precursors through an N- ... ...

Abstract	The wide range of moieties installed in ribosomally synthesized and post-translationally modified peptides (RiPPs) suggests largely untapped potential for protein engineering. However, many RiPP maturases recognize target peptide precursors through an N-terminal leader sequence that is challenging to adapt to proteins. We have recently reported a family of enzymes that splice XYG sites in RiPPs to install α-keto-β-amino acids. Backbone modifications influence diverse protein properties, yet the toolkit to install β-amino acids is limited. Here we report their leader-independent incorporation into proteins in E. coli. Integrating an 11-residue splice tag into six different proteins permitted the site-selective introduction of β-residues in vivo. The motif fusion at C-, N-terminal, and internal positions yielded various β-residues. Our approach complements the few existing methods to introduce β-amino acids or ketone-bearing moieties, suggesting diverse applications in chemical biology.
MeSH term(s)	Amino Acids/metabolism ; Escherichia coli/metabolism ; Peptides/chemistry ; Protein Processing, Post-Translational
Chemical Substances	Amino Acids ; Peptides
Language	English
Publishing date	2022-05-31
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.202202695
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Article: The hidden enzymology of bacterial natural product biosynthesis.

Scott, Thomas A / Piel, Jörn

Nature reviews. Chemistry

2019 Volume 3, Issue 7, Page(s) 404–425

Abstract: Bacterial natural products display astounding structural diversity, which, in turn, endows them with a remarkable range of biological activities that are of significant value to modern society. Such structural features are generated by biosynthetic ... ...

Abstract	Bacterial natural products display astounding structural diversity, which, in turn, endows them with a remarkable range of biological activities that are of significant value to modern society. Such structural features are generated by biosynthetic enzymes that construct core scaffolds or perform peripheral modifications, and can thus define natural product families, introduce pharmacophores and permit metabolic diversification. Modern genomics approaches have greatly enhanced our ability to access and characterize natural product pathways via sequence-similarity-based bioinformatics discovery strategies. However, many biosynthetic enzymes catalyse exceptional, unprecedented transformations that continue to defy functional prediction and remain hidden from us in bacterial (meta)genomic sequence data. In this Review, we highlight exciting examples of unusual enzymology that have been uncovered recently in the context of natural product biosynthesis. These suggest that much of the natural product diversity, including entire substance classes, awaits discovery. New approaches to lift the veil on the cryptic chemistries of the natural product universe are also discussed.
Language	English
Publishing date	2019-06-12
Publishing country	England
Document type	Journal Article
ISSN	2397-3358
ISSN	2397-3358
DOI	10.1038/s41570-019-0107-1
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Article ; Online: Characterization of an Unusual α-Oxoamine Synthase Off-Loading Domain from a Cyanobacterial Type I Fatty Acid Synthase.

Ogonkov, Andrei / Dieterich, Cora L / Meoded, Roy A / Piel, Jörn / Fraley, Amy E / Sasso, Severin

Chembiochem : a European journal of chemical biology

2023 Volume 24, Issue 18, Page(s) e202300209

Abstract: Type I fatty acid synthases (FASs) are known from higher eukaryotes and fungi. We report the discovery of FasT, a rare type I FAS from the cyanobacterium Chlorogloea sp. CCALA695. FasT possesses an unusual off-loading domain, which was heterologously ... ...

Abstract	Type I fatty acid synthases (FASs) are known from higher eukaryotes and fungi. We report the discovery of FasT, a rare type I FAS from the cyanobacterium Chlorogloea sp. CCALA695. FasT possesses an unusual off-loading domain, which was heterologously expressed in E. coli and found to act as an α-oxoamine synthase (AOS) in vitro. Similar to serine palmitoyltransferases from sphingolipid biosynthesis, the AOS off-loading domain catalyzes a decarboxylative Claisen condensation between l-serine and a fatty acyl thioester. While the AOS domain was strictly specific for l-serine, thioesters with saturated fatty acyl chains of six carbon atoms and longer were tolerated, with the highest activity observed for stearoyl-coenzyme A (C
MeSH term(s)	Escherichia coli ; Serine C-Palmitoyltransferase ; Fatty Acids ; Serine
Chemical Substances	Serine C-Palmitoyltransferase (EC 2.3.1.50) ; Fatty Acids ; Serine (452VLY9402)
Language	English
Publishing date	2023-05-25
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.202300209
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Article ; Online: Computational studies on the sterol-like cyclization of a monodomain class II terpene cyclase.

Hess, B Andes / Piel, Jörn / Smentek, Lidia

Organic & biomolecular chemistry

2021 Volume 19, Issue 48, Page(s) 10647–10651

Abstract: Recently the first example of a class II terpene cyclase comprised of only a single domain was reported. Class II synthases are a diverse group of enzymes that catalyze exceptionally complex reactions, including the remarkable cyclization of steroids. ... ...

Abstract	Recently the first example of a class II terpene cyclase comprised of only a single domain was reported. Class II synthases are a diverse group of enzymes that catalyze exceptionally complex reactions, including the remarkable cyclization of steroids. This discovery of a single-domain enzyme being able to catalyze a steroid-like product contradicted the long-held tenet that complex class II cyclizations required double-domain enzymes. The proposed mechanism for the sterol-like cyclization of a monodomain class II terpene cyclase was studied computationally by using density functional theory (DFT). The complete pathway for the conversion of 5-geranyl-3,4-dihydroxybenzoate to the steroid-like pentacyclic product merosterolic acid A was elucidated. The formation of a tricyclic carbocation intermediate with three cyclohexane rings was found to be a concerted, but asynchronous, cyclization. The formation of the fourth ring proceeds with a low energy activation Friedel-Crafts reaction. Subsequent deprotonation of this pentacyclic system gave as the final product merosterolic acid. The overall conversion was found to be highly exothermic due to the conversion of three C-C double bonds to C-C single bonds.
MeSH term(s)	Terpenes
Chemical Substances	Terpenes
Language	English
Publishing date	2021-12-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2097583-1
ISSN	1477-0539 ; 1477-0520
ISSN (online)	1477-0539
ISSN	1477-0520
DOI	10.1039/d1ob02018h
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Article ; Online: A roadmap for metagenomic enzyme discovery.

Robinson, Serina L / Piel, Jörn / Sunagawa, Shinichi

Natural product reports

2021 Volume 38, Issue 11, Page(s) 1994–2023

Abstract: Covering: up to 2021Metagenomics has yielded massive amounts of sequencing data offering a glimpse into the biosynthetic potential of the uncultivated microbial majority. While genome-resolved information about microbial communities from nearly every ... ...

Abstract	Covering: up to 2021Metagenomics has yielded massive amounts of sequencing data offering a glimpse into the biosynthetic potential of the uncultivated microbial majority. While genome-resolved information about microbial communities from nearly every environment on earth is now available, the ability to accurately predict biocatalytic functions directly from sequencing data remains challenging. Compared to primary metabolic pathways, enzymes involved in secondary metabolism often catalyze specialized reactions with diverse substrates, making these pathways rich resources for the discovery of new enzymology. To date, functional insights gained from studies on environmental DNA (eDNA) have largely relied on PCR- or activity-based screening of eDNA fragments cloned in fosmid or cosmid libraries. As an alternative, shotgun metagenomics holds underexplored potential for the discovery of new enzymes directly from eDNA by avoiding common biases introduced through PCR- or activity-guided functional metagenomics workflows. However, inferring new enzyme functions directly from eDNA is similar to searching for a 'needle in a haystack' without direct links between genotype and phenotype. The goal of this review is to provide a roadmap to navigate shotgun metagenomic sequencing data and identify new candidate biosynthetic enzymes. We cover both computational and experimental strategies to mine metagenomes and explore protein sequence space with a spotlight on natural product biosynthesis. Specifically, we compare
MeSH term(s)	Amino Acid Sequence ; Biological Products/metabolism ; Catalytic Domain ; Cytochrome P-450 Enzyme System/chemistry ; Cytochrome P-450 Enzyme System/physiology ; Enzymes/chemistry ; Enzymes/isolation & purification ; Machine Learning ; Metagenomics/methods ; Microbiota ; Phylogeny
Chemical Substances	Biological Products ; Enzymes ; Cytochrome P-450 Enzyme System (9035-51-2)
Language	English
Publishing date	2021-11-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2002546-4
ISSN	1460-4752 ; 0265-0568
ISSN (online)	1460-4752
ISSN	0265-0568
DOI	10.1039/d1np00006c
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Article ; Online: Comparative Genomics Underlines Multiple Roles of Profftella, an Obligate Symbiont of Psyllids: Providing Toxins, Vitamins, and Carotenoids.

Nakabachi, Atsushi / Piel, Jörn / Malenovský, Igor / Hirose, Yuu

Genome biology and evolution

2020 Volume 12, Issue 11, Page(s) 1975–1987

Abstract: The Asian citrus psyllid Diaphorina citri (Insecta: Hemiptera: Psylloidea), a serious pest of citrus species worldwide, harbors vertically transmitted intracellular mutualists, Candidatus Profftella armatura (Profftella_DC, Gammaproteobacteria: ... ...

Abstract	The Asian citrus psyllid Diaphorina citri (Insecta: Hemiptera: Psylloidea), a serious pest of citrus species worldwide, harbors vertically transmitted intracellular mutualists, Candidatus Profftella armatura (Profftella_DC, Gammaproteobacteria: Burkholderiales) and Candidatus Carsonella ruddii (Carsonella_DC, Gammaproteobacteria: Oceanospirillales). Whereas Carsonella_DC is a typical nutritional symbiont, Profftella_DC is a unique defensive symbiont with organelle-like features, including intracellular localization within the host, perfect infection in host populations, vertical transmission over evolutionary time, and drastic genome reduction down to much less than 1 Mb. Large parts of the 460-kb genome of Profftella_DC are devoted to genes for synthesizing a polyketide toxin; diaphorin. To better understand the evolution of this unusual symbiont, the present study analyzed the genome of Profftella_Dco, a sister lineage to Profftella_DC, using Diaphorina cf. continua, a host psyllid congeneric with D. citri. The genome of coresiding Carsonella (Carsonella_Dco) was also analyzed. The analysis revealed nearly perfect synteny conservation in these genomes with their counterparts from D. citri. The substitution rate analysis further demonstrated genomic stability of Profftella which is comparable to that of Carsonella. Profftella_Dco and Profftella_DC shared all genes for the biosynthesis of diaphorin, hemolysin, riboflavin, biotin, and carotenoids, underlining multiple roles of Profftella, which may contribute to stabilizing symbiotic relationships with the host. However, acyl carrier proteins were extensively amplified in polyketide synthases DipP and DipT for diaphorin synthesis in Profftella_Dco. This level of acyl carrier protein augmentation, unprecedented in modular polyketide synthases of any known organism, is not thought to influence the polyketide structure but may improve the synthesis efficiency.
MeSH term(s)	Amino Acid Sequence ; Animals ; Biological Evolution ; Carotenoids/metabolism ; Gammaproteobacteria/chemistry ; Gammaproteobacteria/genetics ; Gammaproteobacteria/metabolism ; Genome, Bacterial ; Hemiptera/microbiology ; Hemolysin Proteins/chemistry ; Hemolysin Proteins/genetics ; Hemolysin Proteins/metabolism ; Mutation Rate ; Polyketides/metabolism ; Symbiosis ; Vitamins/genetics ; Vitamins/metabolism
Chemical Substances	Hemolysin Proteins ; Polyketides ; Vitamins ; Carotenoids (36-88-4)
Keywords	covid19
Language	English
Publishing date	2020-07-30
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2495328-3
ISSN	1759-6653 ; 1759-6653
ISSN (online)	1759-6653
ISSN	1759-6653
DOI	10.1093/gbe/evaa175
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