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

• support a Syn-BNP based PK discovery campaign. Future directions 4: Natural products with more complex biosynthetic logic Type I NRPs and PKs, as well as many sub-families of ribosomally synthesized and post-translationally modified peptides (RiPPs), are readily amenable to chemical structure metagenomics

• alkylmalonate BBs. While predicting most modifications de novo is not yet built into existing algorithms, it is often possible to work them out based on chemical structure context, background knowledge, and educated guesses. For example, cyclodehydration, a feature frequently seen in both NRPs and RiPPs [87

• thiazo moieties come from cysteines. The same requirement applies to the formation of dehydroalanine and dehydrobutyrine moieties. These chemical principles hold true even though the tailoring enzymes for these modifications in NRPs and RiPPs are nonhomologous [88][89]. Some types of modifications are

Discovery of antimicrobial peptides clostrisin and cellulosin from Clostridium: insights into their structures, co-localized biosynthetic gene clusters, and antibiotic activity

• Moisés Alejandro Alejo Hernandez,
• Katia Pamela Villavicencio Sánchez,
• Rosendo Sánchez Morales,
• Karla Georgina Hernández-Magro Gil,
• David Silverio Moreno-Gutiérrez,
• Eddie Guillermo Sanchez-Rueda,
• Yanet Teresa-Cruz,
• Brian Choi,
• Armando Hernández Garcia,
• Alba Romero-Rodríguez,
• Oscar Juárez,
• Siseth Martínez-Caballero,
• Mario Figueroa and
• Corina-Diana Ceapă

Beilstein J. Org. Chem. 2024, 20, 1800–1816, doi:10.3762/bjoc.20.159

• including some resistant to existing antibiotics [9]. Thus, peptides, including ribosomally synthesized and post-translationally modified peptides (RiPPs), have been regarded as important sources of antibiotics, both historically and through recent discoveries [10]. Lanthipeptides are a class of RiPPs

• antibiotics against drug-resistant pathogens. Although certain RiPPs with activity against Clostridia have been described [31], the characterization of complete gene clusters encoding for lantibiotics, using their native biosynthetic machinery and not that of nisin or of other non-native peptides, as well as

• the Clostridium genus encountered 17 protein sequences associated with 12 genomes. After analyzing these genomes with AntiSMASH [3], we identified 150 different BGCs of specialized metabolites from different biosynthetic classes. The RiPPs accounted for 36% of these (54 clusters). A total of 14 BGCs

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• engineered P450 enzymes catalyzed the site- and stereoselective oxidative modifications enabling further chemical transformations. Since the scaffolds of terpenes and ribosomally synthesized and post-translationally modified peptides (RiPPs) are first biosynthesized and then modified, the strategy of late

• , efficiency, and robustness of these biocatalysts are expected to enhance their usefulness and generality as synthetic tools. Apart from oxygenated terpenes and RiPPs, chemo-enzymatic approaches for polyketides and non-ribosomal peptides (NRPs) are considered more suitable for the second and third strategies

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• -translational modifications; ribosomal peptides; SAM-dependent enzymes; Introduction In the complex landscape of natural product biosynthesis, ribosomally synthesised and post-translationally modified peptides (RiPPs) stand out as a fascinating class of compounds with both structural diversity and unique

• resulting natural products with a spectrum of chemical complexity, contributing to the broad range of biological activities exhibited by RiPPs. Bioactivities attributed to RiPPs include a wide range of effects, such as antibiotic, antifungal, antiviral, antiparasitic, antitumour, analgesic, anti

• -inflammatory, antidiabetic, antihypertensive, and anti-parkinsonian [7][8]. This diverse profile makes RiPPs particularly valuable for various therapeutic and medicinal applications. Generally, peptide natural products are promising drug development candidates due to their intermediate molecular weight, which

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• publicly available which are typically 5 Mbp in size. Computational mining these genomes with antiSMASH reveals that these bacteria, though not endowed with the biosynthetic prowess of actinomycetes, do still possess BGCs encoding NRPS-derived peptides, polyketides, RiPPs, and siderophores [4][147]. A

Mining raw plant transcriptomic data for new cyclopeptide alkaloids

• Draco Kriger,
• Michael A. Pasquale,
• Brigitte G. Ampolini and
• Jonathan R. Chekan

Beilstein J. Org. Chem. 2024, 20, 1548–1559, doi:10.3762/bjoc.20.138

• transcriptomic data sets, we uncover the potential distribution of split burpitide precursor peptides in Streptophyta. Metabolomic analysis of target plants confirms our bioinformatic predictions of new cyclopeptide alkaloids from both known and new sources. Keywords: burpitides; natural products; plants; RiPPs

• prevalent in plants [4]. Like all known plant peptides, burpitides fall under the ribosomally synthesized and post-translationally modified peptides (RiPPs) superclass of natural products (Figure 1). The typical pathway for a RiPP starts with a precursor peptide made by the ribosome that undergoes post

• biosynthetic enzymes. Ultimately proteolysis releases the modified core peptide as the mature RiPP natural product [5][6]. In the case of the newly described burpitide family of RiPPs, the defining feature is the presence of amino acid side-chain crosslinks installed by a copper-dependent burpitide cyclase [4

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• , terpene cyclases generate the oftentimes multicyclic, hydrocarbon scaffold via a carbocation-mediated cascade reaction [30]. Terpene cyclases are obligatory components of canonical terpene pathways and are used to identify terpene BGCs (Figure 3B) [30][31]. RiPPs, on the other hand, lack genes that are

• mining tools Some NP BGCs contain solely family-specific features, and lack universal class-specific signature sequences. In these cases, only members of the same subfamily can be identified via pHMMs. An example of the latter are RiPPs that are the most rapidly expanding NP subclass. Eighteen new RiPP

• are limited when it comes to solving complex problems [72]. An example of an advanced combination of different approaches and methods for the identification of RiPPs is the Data-driven Exploratory Class-independent RiPP TrackER (decRiPPter) [65]. decRiPPter uses a support vector machine algorithm

Posttranslational isoprenylation of tryptophan in bacteria

• Masahiro Okada,
• Tomotoshi Sugita and
• Ikuro Abe

Beilstein J. Org. Chem. 2017, 13, 338–346, doi:10.3762/bjoc.13.37

• (RIPPs), a conserved recognition motif in the N-terminal leader region of the precursor peptide enables the enzymatic modification of the C-terminal core peptide, and then the leader amino acids are frequently cleaved [2]. However, there is no obvious sequence within the N-terminal region of the ComX

• has occurred at an internal tryptophan residue of the precursor peptide. Kawaguchipeptin A Apart from the ComX pheromones, post-translational dimethylallylations of the tyrosine, threonine, serine, and tryptophan residues of cyclic peptides from cyanobacteria were reported [49][50][51]. The RiPPs

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• Andrew W. Truman Department of Molecular Microbiology, John Innes Centre, Colney Lane, Norwich, NR4 7UH, UK 10.3762/bjoc.12.120 Abstract Ribosomally synthesised and post-translationally modified peptides (RiPPs) are a large class of natural products that are remarkably chemically diverse given an

• intrinsic requirement to be assembled from proteinogenic amino acids. The vast chemical space occupied by RiPPs means that they possess a wide variety of biological activities, and the class includes antibiotics, co-factors, signalling molecules, anticancer and anti-HIV compounds, and toxins. A considerable

• heterocyclisation to form thiazolines or oxazolines, and radical-mediated reactions between unactivated carbons. Future prospects for RiPP pathway discovery and characterisation will also be highlighted. Keywords: biosynthesis; cyclisation; enzymes; peptides; RiPPs; Introduction Nature employs a number of routes