scholarly journals Thiocysteine lyases as polyketide synthase domains installing hydropersulfide into natural products and a hydropersulfide methyltransferase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Song Meng ◽  
Andrew D. Steele ◽  
Wei Yan ◽  
Guohui Pan ◽  
Edward Kalkreuter ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Assembly Line ◽  
Polyketide Synthase ◽  
Genome Mining ◽  
Assembly Lines ◽  
Biologically Relevant ◽  
Peptide Synthetase ◽  
Adenosyl Methionine

AbstractNature forms S-S bonds by oxidizing two sulfhydryl groups, and no enzyme installing an intact hydropersulfide (-SSH) group into a natural product has been identified to date. The leinamycin (LNM) family of natural products features intact S-S bonds, and previously we reported an SH domain (LnmJ-SH) within the LNM hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line as a cysteine lyase that plays a role in sulfur incorporation. Here we report the characterization of an S-adenosyl methionine (SAM)-dependent hydropersulfide methyltransferase (GnmP) for guangnanmycin (GNM) biosynthesis, discovery of hydropersulfides as the nascent products of the GNM and LNM hybrid NRPS-PKS assembly lines, and revelation of three SH domains (GnmT-SH, LnmJ-SH, and WsmR-SH) within the GNM, LNM, and weishanmycin (WSM) hybrid NRPS-PKS assembly lines as thiocysteine lyases. Based on these findings, we propose a biosynthetic model for the LNM family of natural products, featuring thiocysteine lyases as PKS domains that directly install a -SSH group into the GNM, LNM, or WSM polyketide scaffold. Genome mining reveals that SH domains are widespread in Nature, extending beyond the LNM family of natural products. The SH domains could also be leveraged as biocatalysts to install an -SSH group into other biologically relevant scaffolds.

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

2011 ◽  
Vol 7 ◽  
pp. 1622-1635 ◽  
Author(s):  
Jan-Christoph Kehr ◽  
Douglas Gatte Picchi ◽  
Elke Dittmann
Keyword(s):  
Natural Products ◽  
Synthetic Biology ◽  
Natural Product ◽  
Bioactive Compounds ◽  
Polyketide Synthase ◽  
Biosynthetic Pathways ◽  
Peptide Synthetase ◽  
Biochemical Studies ◽  
Terrestrial Habitats ◽  
The Individual

Cyanobacteria are prolific producers of natural products. Investigations into the biochemistry responsible for the formation of these compounds have revealed fascinating mechanisms that are not, or only rarely, found in other microorganisms. In this article, we survey the biosynthetic pathways of cyanobacteria isolated from freshwater, marine and terrestrial habitats. We especially emphasize modular 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 obtained from the biochemical studies of cyanobacterial pathways can inspire the development of concepts for the design of bioactive compounds by synthetic-biology approaches in the future.

scholarly journals Biosynthesis of a Complex Yersiniabactin-Like Natural Product via themicLocus in Phytopathogen Ralstonia solanacearum

2011 ◽  
Vol 77 (17) ◽  
pp. 6117-6124 ◽  
Author(s):  
Martin F. Kreutzer ◽  
Hirokazu Kage ◽  
Peter Gebhardt ◽  
Barbara Wackler ◽  
Hans P. Saluz ◽  
...  
Keyword(s):  
Natural Product ◽  
Gene Cluster ◽  
Ralstonia Solanacearum ◽  
Insertional Mutagenesis ◽  
Polyketide Synthase ◽  
Genome Mining ◽  
Content Type ◽  
A Genome ◽  
Iron Deficient ◽  
Peptide Synthetase

ABSTRACTA genome mining study in the plant pathogenic bacteriumRalstonia solanacearumGMI1000 unveiled a polyketide synthase/nonribosomal peptide synthetase gene cluster putatively involved in siderophore biosynthesis. Insertional mutagenesis confirmed the respective locus to be operational under iron-deficient conditions and spurred the isolation of the associated natural product. Bioinformatic analyses of the gene cluster facilitated the structural characterization of this compound, which was subsequently identified as the antimycoplasma agent micacocidin. The metal-chelating properties of micacocidin were evaluated in competition experiments, and the cellular uptake of gallium-micacocidin complexes was demonstrated inR. solanacearumGMI1000, indicating a possible siderophore role. Comparative genomics revealed a conservation of the micacocidin gene cluster in defined, but globally dispersed phylotypes ofR. solanacearum.

scholarly journals Avant-garde assembly-line biosynthesis expands diversity of cyclic lipodepsipeptide products

2019 ◽  
Author(s):  
Jia Jia Zhang ◽  
Xiaoyu Tang ◽  
Tao Huan ◽  
Avena C. Ross ◽  
Bradley S. Moore
Keyword(s):  
Assembly Line ◽  
Polyketide Synthase ◽  
Structural Features ◽  
Chemical Diversity ◽  
Chain Extension ◽  
Assembly Lines ◽  
Avant Garde ◽  
Peptide Synthetase ◽  
Domain Interactions ◽  
Catalytic Cycles

Modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzymatic assembly lines are large and dynamic protein machines that generally undergo a linear progression of catalytic cycles via a series of enzymatic domains organized into independent modules. Here we report the heterologous reconstitution and comprehensive characterization of two hybrid NRPS-PKS assembly lines that defy many standard rules of assembly-line biosynthesis to generate a large combinatorial library of cyclic lipodepsipeptide protease inhibitors called thalassospiramides. We generate a series of precise domain-inactivating mutations in thalassospiramide assembly lines and present compelling evidence for an unprecedented biosynthetic model that invokes inter-module substrate activation and tailoring, module skipping, and pass-back chain extension, whereby the ability to pass the growing chain back to a preceding module is flexible and substrate-driven. Expanding bidirectional inter-module domain interactions could represent a viable mechanism for generating chemical diversity without increasing the size of biosynthetic assembly lines and raises new questions regarding our understanding of the structural features of multi-modular megaenzymes.

scholarly journals A Multi-Omics Characterization of the Natural Product Potential of Tropical Filamentous Marine Cyanobacteria

Marine Drugs ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. 20
Author(s):  
Tiago Leão ◽  
Mingxun Wang ◽  
Nathan Moss ◽  
Ricardo da Silva ◽  
Jon Sanders ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Genome Mining ◽  
Gene Clusters ◽  
Microbial Interactions ◽  
Marine Cyanobacteria ◽  
Pharmaceutical Drugs ◽  
Genes Encoding ◽  
Microbial Natural Products

Microbial natural products are important for the understanding of microbial interactions, chemical defense and communication, and have also served as an inspirational source for numerous pharmaceutical drugs. Tropical marine cyanobacteria have been highlighted as a great source of new natural products, however, few reports have appeared wherein a multi-omics approach has been used to study their natural products potential (i.e., reports are often focused on an individual natural product and its biosynthesis). This study focuses on describing the natural product genetic potential as well as the expressed natural product molecules in benthic tropical cyanobacteria. We collected from several sites around the world and sequenced the genomes of 24 tropical filamentous marine cyanobacteria. The informatics program antiSMASH was used to annotate the major classes of gene clusters. BiG-SCAPE phylum-wide analysis revealed the most promising strains for natural product discovery among these cyanobacteria. LCMS/MS-based metabolomics highlighted the most abundant molecules and molecular classes among 10 of these marine cyanobacterial samples. We observed that despite many genes encoding for peptidic natural products, peptides were not as abundant as lipids and lipopeptides in the chemical extracts. Our results highlight a number of highly interesting biosynthetic gene clusters for genome mining among these cyanobacterial samples.

scholarly journals Shared PKS modules in biosynthesis of synergistic laxaphycins

2020 ◽  
Author(s):  
LMP Heinilä ◽  
DP Fewer ◽  
J Jokela ◽  
M Wahlsten ◽  
A Jortikka ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Polyketide Synthase ◽  
Biosynthetic Gene Cluster ◽  
Future Research ◽  
Biosynthetic Pathways ◽  
Biosynthetic Gene ◽  
Wide Range ◽  
Peptide Synthetase ◽  
Antiproliferative Activities

AbstractCyanobacteria produce a wide range of lipopeptides that exhibit potent membrane-disrupting activities. Laxaphycins consist of two families of structurally distinct macrocyclic lipopeptides that act in a synergistic manner to produce antifungal and antiproliferative activities. Laxaphycins are produced by range of cyanobacteria but their biosynthetic origins remain unclear. Here, we identified the biosynthetic pathways responsible for the biosynthesis of the laxaphycins produced by Scytonema hofmannii PCC 7110. We show that these laxaphycins, called scytocyclamides, are produced by this cyanobacterium and are encoded in a single biosynthetic gene cluster with shared polyketide synthase enzymes initiating two distinct non-ribosomal peptide synthetase pathways. To our knowledge, laxaphycins are the first clearly distinct polyketide synthase and non-ribosomal peptide synthetase hybrid natural products with shared branched biosynthesis. The unusual mechanism of shared enzymes synthesizing two distinct types of products may aid future research in identifying and expressing natural product biosynthetic pathways and in expanding the known biosynthetic logic of this important family of natural products.

scholarly journals Natural product fragment combination to performance-diverse pseudo-natural products

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael Grigalunas ◽  
Annina Burhop ◽  
Sarah Zinken ◽  
Axel Pahl ◽  
José-Manuel Gally ◽  
...  
Keyword(s):  
Natural Products ◽  
Product Design ◽  
Natural Product ◽  
Chemical Space ◽  
Biological Evaluation ◽  
Product Structure ◽  
Biologically Relevant ◽  
Biologically Relevant Chemical Space

AbstractNatural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.

scholarly journals The Tripod for Bacterial Natural Product Discovery: Genome Mining, Silent Pathway Induction, and Mass Spectrometry-Based Molecular Networking

mSystems ◽  
2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Daniela B. B. Trivella ◽  
Rafael de Felicio
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Natural Product ◽  
Biosynthetic Pathway ◽  
Genome Mining ◽  
Chemical Compounds ◽  
Gene Clusters ◽  
Tandem Mass ◽  
Molecular Networking ◽  
Natural Product Discovery

ABSTRACT Natural products are the richest source of chemical compounds for drug discovery. Particularly, bacterial secondary metabolites are in the spotlight due to advances in genome sequencing and mining, as well as for the potential of biosynthetic pathway manipulation to awake silent (cryptic) gene clusters under laboratory cultivation. Further progress in compound detection, such as the development of the tandem mass spectrometry (MS/MS) molecular networking approach, has contributed to the discovery of novel bacterial natural products. The latter can be applied directly to bacterial crude extracts for identifying and dereplicating known compounds, therefore assisting the prioritization of extracts containing novel natural products, for example. In our opinion, these three approaches—genome mining, silent pathway induction, and MS-based molecular networking—compose the tripod for modern bacterial natural product discovery and will be discussed in this perspective.

Protein–protein interactions in polyketide synthase–nonribosomal peptide synthetase hybrid assembly lines

2018 ◽  
Vol 35 (11) ◽  
pp. 1185-1209 ◽  
Author(s):  
Akimasa Miyanaga ◽  
Fumitaka Kudo ◽  
Tadashi Eguchi
Keyword(s):  
Protein Interactions ◽  
Polyketide Synthase ◽  
Nonribosomal Peptide Synthetase ◽  
Hybrid Assembly ◽  
Protein Protein Interactions ◽  
Assembly Lines ◽  
Nonribosomal Peptide ◽  
Peptide Synthetase

The protein–protein interactions in polyketide synthase–nonribosomal peptide synthetase hybrids are summarized and discussed.

scholarly journals Genomic analysis of siderophore β-hydroxylases reveals divergent stereocontrol and expands the condensation domain family

2019 ◽  
Vol 116 (40) ◽  
pp. 19805-19814 ◽  
Author(s):  
Zachary L. Reitz ◽  
Clifford D. Hardy ◽  
Jaewon Suk ◽  
Jean Bouvet ◽  
Alison Butler
Keyword(s):  
Predictive Power ◽  
Genome Mining ◽  
Genomic Analysis ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Peptide Synthetase ◽  
Condensation Domain

Genome mining of biosynthetic pathways streamlines discovery of secondary metabolites but can leave ambiguities in the predicted structures, which must be rectified experimentally. Through coupling the reactivity predicted by biosynthetic gene clusters with verified structures, the origin of the β-hydroxyaspartic acid diastereomers in siderophores is reported herein. Two functional subtypes of nonheme Fe(II)/α-ketoglutarate–dependent aspartyl β-hydroxylases are identified in siderophore biosynthetic gene clusters, which differ in genomic organization—existing either as fused domains (IβHAsp) at the carboxyl terminus of a nonribosomal peptide synthetase (NRPS) or as stand-alone enzymes (TβHAsp)—and each directs opposite stereoselectivity of Asp β-hydroxylation. The predictive power of this subtype delineation is confirmed by the stereochemical characterization of β-OHAsp residues in pyoverdine GB-1, delftibactin, histicorrugatin, and cupriachelin. The l-threo (2S, 3S) β-OHAsp residues of alterobactin arise from hydroxylation by the β-hydroxylase domain integrated into NRPS AltH, while l-erythro (2S, 3R) β-OHAsp in delftibactin arises from the stand-alone β-hydroxylase DelD. Cupriachelin contains both l-threo and l-erythro β-OHAsp, consistent with the presence of both types of β-hydroxylases in the biosynthetic gene cluster. A third subtype of nonheme Fe(II)/α-ketoglutarate–dependent enzymes (IβHHis) hydroxylates histidyl residues with l-threo stereospecificity. A previously undescribed, noncanonical member of the NRPS condensation domain superfamily is identified, named the interface domain, which is proposed to position the β-hydroxylase and the NRPS-bound amino acid prior to hydroxylation. Through mapping characterized β-OHAsp diastereomers to the phylogenetic tree of siderophore β-hydroxylases, methods to predict β-OHAsp stereochemistry in silico are realized.

scholarly journals Cheminformatics Analysis of Natural Product Scaffolds: Comparison of Scaffolds Produced by Animals, Plants, Fungi and Bacteria

2020 ◽  
Author(s):  
Peter Ertl ◽  
Tim Schuhmann
Keyword(s):  
Natural Products ◽  
Natural Selection ◽  
Natural Product ◽  
Selection Process ◽  
Structural Features ◽  
New Drugs ◽  
Large Database ◽  
Biologically Relevant ◽  
Different Types ◽  
Selection Of

AbstractNatural products (NPs) have evolved over a very long natural selection process to form optimal interactions with biologically relevant macromolecules. NPs are therefore an extremely useful source of inspiration for the design of new drugs. In the present study we report the results of a cheminformatics analysis of a large database of NP structures focusing on their scaffolds. First, general differences between NP scaffolds and scaffolds from synthetic molecules are discussed, followed by a comparison of the properties of scaffolds produced by different types of organisms. Scaffolds produced by plants are the most complex and those produced by bacteria differ in many structural features from scaffolds produced by other organisms. The results presented here may be used as a guidance in selection of scaffolds for the design of novel NP-like bioactive structures or NP-inspired libraries.

Sign in / Sign up

Export Citation Format

Share Document