Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• silico to avoid rediscovery. They are the cornerstone of chemical structure metagenomics; a few examples in this area of research are described below. NRP biosynthesis and structure prediction NRPs are biosynthesized by either type I or II nonribosomal peptide synthetase (NRPS) [50][51]. Type I NRPS is a

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• and multifunctional enzymatic assembly, nonribosomal peptide synthases (NRPS), polyketide synthases (PKS), and hybrid NRPS/PKS systems, which are organized into sets of functional domains known as modules and function through a similar mechanism [9][10][11][12]. Each NRPS module is composed of three

Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells

• Fumihiro Ishikawa,
• Sho Konno,
• Hideaki Kakeya and
• Genzoh Tanabe

Beilstein J. Org. Chem. 2024, 20, 445–451, doi:10.3762/bjoc.20.39

• synthetase A (GrsA) in the gramicidin S-producer Aneurinibacillus migulanus ATCC 9999, providing an alternative scaffold to develop novel A-domain inhibitors. Keywords: adenylation domain inhibitor; gramicidin S synthetase; natural product; nonribosomal peptide; nonribosomal peptide synthetase

• biosynthesis by using small molecules can help to elucidate their natural functions and their potential as therapeutic targets. NRPs are synthesized by large, versatile, and multifunctional proteins called nonribosomal peptide synthetases (NRPSs), which are composed of multiple modules and subdivided domains

• -specific A-domain; A2, ʟ-Pro-specific A-domain; A3, ʟ-Val-specific A-domain; A4, ʟ-Orn-specific A-domain; A5, ʟ-Leu-specific A-domain; E, epimerization domain; C, condensation domain; TE, thioesterase domain. (A) Adenylation reaction in a nonribosomal peptide synthetase. (B) Structures of aminoacyl-AMS

Secondary metabolites of Diaporthe cameroonensis, isolated from the Cameroonian medicinal plant Trema guineensis

• Bel Youssouf G. Mountessou,
• Élodie Gisèle M. Anoumedem,
• Blondelle M. Kemkuignou,
• Yasmina Marin-Felix,
• Frank Surup,
• Marc Stadler and
• Simeon F. Kouam

Beilstein J. Org. Chem. 2023, 19, 1555–1561, doi:10.3762/bjoc.19.112

• great structural variability such as polyketides, terpenoids, polyketide synthase–nonribosomal peptide synthetase (PKS–NRPS) alkaloids, and cytochalasins, which have been considered as taxonomic markers of the genus [7][8][9][10]. However, it is worthwhile to mention that the name Phomopsis should no

Enzymes in biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1131–1132, doi:10.3762/bjoc.18.116

• proceed through multistep cationic cascade reactions and usually produce a polycyclic terpene hydrocarbon or alcohol with multiple stereogenic centers. While these transformations require only a single enzyme, polyketide and nonribosomal peptide biosyntheses are catalyzed by megasynthases that follow an

Secondary metabolites of Bacillus subtilis impact the assembly of soil-derived semisynthetic bacterial communities

• Heiko T. Kiesewalter,
• Carlos N. Lozano-Andrade,
• Mikael L. Strube and
• Ákos T. Kovács

Beilstein J. Org. Chem. 2020, 16, 2983–2998, doi:10.3762/bjoc.16.248

• Bacillus spp. produce various SMs [33][34]. The most prominent and bioactive SMs are nonribosomal peptides (NRPs), of which isoforms belong to the families of surfactins, fengycins, or iturins [35][36] (Figure 1). They are biosynthesised by large enzyme complexes, nonribosomal peptide synthetases (NRPSs

Nocarimidazoles C and D, antimicrobial alkanoylimidazoles from a coral-derived actinomycete Kocuria sp.: application of ¹J_C,H coupling constants for the unequivocal determination of substituted imidazoles and stereochemical diversity of anteisoalkyl chains in microbial metabolites

• Md. Rokon Ul Karim,
• Enjuro Harunari,
• Amit Raj Sharma,
• Naoya Oku,
• Kazuaki Akasaka,
• Daisuke Urabe,
• Mada Triandala Sibero and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 2719–2727, doi:10.3762/bjoc.16.222

• genomic information suggests the presence of biosynthetic genes for nonribosomal peptide synthetase and type III polyketide synthase in some Kocuria strains [18], which leaves a hope for new secondary metabolites. At present, only a few limited structural types of metabolites, including polyamine-derived

Fabclavine diversity in Xenorhabdus bacteria

• Sebastian L. Wenski,
• Harun Cimen,
• Natalie Berghaus,
• Sebastian W. Fuchs,
• Selcuk Hazir and
• Helge B. Bode

Beilstein J. Org. Chem. 2020, 16, 956–965, doi:10.3762/bjoc.16.84

• for bioactive compounds are required, such as the bacterial genera Xenorhabdus or Photorhabdus. In these strains, fabclavines are widely distributed SMs with a broad-spectrum bioactivity. Fabclavines are hybrid SMs derived from nonribosomal peptide synthetases (NRPS), polyunsaturated fatty acid (PUFA

• ]. Fabclavines are hexapeptide/polyketide hybrids derived from nonribosomal peptide synthetases (NRPS) and a polyketide synthase (PKS), which are connected to an unusual polyamine derived from polyunsaturated fatty acid (PUFA) synthases [20]. Beside full-length fabclavines, also shortened derivatives were

Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• . aeruginosa [18]. Biotechnological engineering of producer strains aims to shutdown the natural substrate production and thereby increase the usually poor yields of the mutasynthesis products [19][20]. For bacterial natural products that originate from a polyketide synthase (PKS) or a nonribosomal peptide

• antipseudomonal activity. The biosynthetic pathway for argyrin production in Cystobacter sp. SBCb004 (Arg1, radical SAM-dependent methyltransferase; Arg2/Arg3, nonribosomal peptide synthetases; Arg4, O‑methyltransferase; Arg5, tryptophan 2,3-dioxygenase). The initial tripeptide of the biosynthesis of the argyrins

• (Supporting Information File 1, Figure S2). To exclude the possibility of inefficient mutasynthon permeability through the bacterial membrane, we decided to repeat the mutasynthesis experiment in vitro using the cell lysate of the respective arg2 deletion mutant. The in vitro reconstitution of nonribosomal

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• thiotemplated assembly lines, such as type I polyketide synthases (PKS) and nonribosomal peptide synthetases (NRPS), are modular, with each module contributing a distinct fragment to the final product’s core structure – a short-chain carboxylic acid (PKS) or an amino acid (NRPS). The modularly defined template

Genomics-inspired discovery of massiliachelin, an agrochelin epimer from Massilia sp. NR 4-1

• Jan Diettrich,
• Hirokazu Kage and
• Markus Nett

Beilstein J. Org. Chem. 2019, 15, 1298–1303, doi:10.3762/bjoc.15.128

• homologs in the mic cluster from R. solanacearum GMI1000 [13]. A closer inspection of the loci shows a strong conservation of two core biosynthesis genes, namely micC and micG. On the other hand, the nonribosomal peptide synthetase (NRPS) gene micH is missing in the Massilia locus. As evidenced by

Chemical structure of cichorinotoxin, a cyclic lipodepsipeptide that is produced by Pseudomonas cichorii and causes varnish spots on lettuce

• Hidekazu Komatsu,
• Takashi Shirakawa,
• Takeo Uchiyama and
• Tsutomu Hoshino

Beilstein J. Org. Chem. 2019, 15, 299–309, doi:10.3762/bjoc.15.27

• assign the D or L configurations for all the amino acids by the feeding experiments. However, we succeeded in proposing the complete stereochemistry of the molecule by careful analysis of the biosynthetic gene cluster (nonribosomal peptide synthetases, NRPS). These results will be reported in due course

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

A non-canonical peptide synthetase adenylates 3-methyl-2-oxovaleric acid for auriculamide biosynthesis

• Daniel Braga,
• Dirk Hoffmeister and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 2766–2770, doi:10.3762/bjoc.12.274

• enzymes. Among them, the non-canonical 199 kDa four-domain nonribosomal peptide synthetase, AulA, is extraordinary in that it features two consecutive adenylation domains. Here, we describe the functional characterization of the recombinantly produced AulA. The observed activation of 3-methyl-2-oxovaleric

• ; nonribosomal peptide synthetase; Findings Herpetosiphon aurantiacus is a filamentous, Gram-negative bacterium with a facultative saprophytic predatory behaviour [1][2]. For a more profound insight into the predation strategies among bacteria, along with the underlying chemistry, the complete genome of H

• microorganism as a promising source of natural products. Genes for nonribosomal peptide synthetases (NRPSs) were found to be preponderant, either solely or organised in combination with polyketide synthase (PKS) genes, representing four and five clusters, respectively. Two PKS and three putative bacteriocin

Antibiotics from predatory bacteria

• Juliane Korp,
• María S. Vela Gurovic and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 594–607, doi:10.3762/bjoc.12.58

• reaction [109][110]. The althiomycin biosynthetic gene cluster was recently identified in M. xanthus DK897 by a combination of retrobiosynthetic analysis and gene inactivation [111]. Two open reading frames (ORFs) encoding for a nonribosomal peptide synthetase (NRPS) and a NRPS/polyketide synthase (PKS

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• B (52) as a model system [51][52][53][54][55]. It was hypothesized that the carbon backbone, which is connected to an amino acid, most likely originates from a polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) hybrid machinery [56]. The discovery of a gene locus for a PKS-NRPS

• basis of the structural similarity between 208 and marinopyrrole A, another secondary metabolite derived from a marine Streptomyces species [156]. The common biosynthetic precursor 206 stems from a mixed nonribosomal peptide synthetase (NRPS)/polyketide synthase (PKS) pathway. The amino acid proline is

Identification and isolation of insecticidal oxazoles from Pseudomonas spp.

• Florian Grundmann,
• Veronika Dill,
• Andrea Dowling,
• Aunchalee Thanwisai,
• Edna Bode,
• Narisara Chantratita,
• Richard ffrench-Constant and
• Helge B. Bode

Beilstein J. Org. Chem. 2012, 8, 749–752, doi:10.3762/bjoc.8.85

• protein or polyketide synthase or nonribosomal peptide synthetase) bound. Supporting Information Supporting Information File 114: General experimental procedures, isolation of the strain and taxonomic identification, cultivation and extraction, isolation, labeling experiments, synthesis, bioactivity

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathways and highlight the unique enzyme mechanisms that were elucidated or can be anticipated for the individual products. We further include ribosomal natural products and UV-absorbing pigments from cyanobacteria. Mechanistic insights

• in microorganisms Microbial natural products of the peptide class are produced by two types of biosynthetic pathways: By giant multi-domain enzymes, the nonribosomal peptide synthetases (NRPS) or by ribosomal synthesis and subsequent post-translational modification and processing. NRPS consist of

• iteratively [16]. Nonribosomal peptide, polyketide and hybrid biosyntheses in cyanobacteria Research on NRPS and PKS gene clusters started almost in parallel in freshwater, marine and terrestrial cyanobacteria. A major trait of cyanobacterial pathways is their hybrid character, i.e., the frequent mixture of

Biosynthesis and function of secondary metabolites

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2011, 7, 1620–1621, doi:10.3762/bjoc.7.190

• polyketide and nonribosomal peptide biosynthetic machineries, which is strongly correlated with the logic of fatty acid biosynthesis as part of the primary metabolism. Insights into the mechanisms of modular polyketide and nonribosomal peptide assembly lines open up the possibility for direct modifications