New insights into the echinocandins and other fungal non-ribosomal peptides and peptaibiotics

2014 ◽  
Vol 31 (10) ◽  
pp. 1348-1375 ◽  
Author(s):  
Gerald Bills ◽  
Yan Li ◽  
Li Chen ◽  
Qun Yue ◽  
Xue-Mei Niu ◽  
...  
Keyword(s):  
Natural Product ◽  
Fungal Metabolites ◽  
Peptide Synthetases ◽  
Product Assembly ◽  
Primary Modality ◽  
Non Ribosomal Peptides

Non-ribosomal peptide synthetases (NRPSs) are a primary modality for fungal peptidic natural product assembly and are responsible for some of the best known, most useful, and most destructive fungal metabolites.

scholarly journals Discovery of Amidotemplated Natural Product Assembly

Biochemistry ◽  
2019 ◽  
Vol 58 (46) ◽  
pp. 4583-4584
Author(s):  
Evelyn M. Molloy ◽  
Maria Dell ◽  
Christian Hertweck
Keyword(s):  
Natural Product ◽  
Product Assembly

Heterologous Expression and Structural Characterisation of a Pyrazinone Natural Product Assembly Line

ChemBioChem ◽  
2012 ◽  
Vol 13 (16) ◽  
pp. 2408-2415 ◽  
Author(s):  
Morgan A. Wyatt ◽  
M. C. Y. Mok ◽  
Murray Junop ◽  
Nathan A. Magarvey
Keyword(s):  
Heterologous Expression ◽  
Natural Product ◽  
Assembly Line ◽  
Structural Characterisation ◽  
Product Assembly

scholarly journals Synthetic Zippers as an Enabling Tool for Engineering of Non-Ribosomal Peptide Synthetases

2020 ◽  
Author(s):  
Kenan A. J. Bozhueyuek ◽  
Jonas Watzel ◽  
Nadya Abbood ◽  
Helge B. Bode
Keyword(s):  
High Titre ◽  
Peptide Libraries ◽  
Divide And Conquer ◽  
Gram Negative ◽  
Peptide Synthetases ◽  
Wide Range ◽  
Single Protein ◽  
Definition Of ◽  
Polypeptide Chains ◽  
Non Ribosomal Peptides

AbstractNon-ribosomal peptide synthetases (NRPSs) are the origin of a wide range of natural products, including many clinically used drugs. Engineering of these often giant biosynthetic machineries to produce novel non-ribosomal peptides (NRPs) at high titre is an ongoing challenge. Here we describe a strategy to functionally combine NRPS fragments of Gram-negative and -positive origin, synthesising novel peptides at titres up to 290 mg l-1. Extending from the recently introduced definition of eXchange Units (XUs), we inserted synthetic zippers (SZs) to split single protein NRPSs into up to three independently expressed and translated polypeptide chains. These synthetic type of NRPS (type S) enables easier access to engineering, overcomes cloning limitations, and provides a simple and rapid approach to building peptide libraries via the combination of different NRPS subunits.One Sentence SummaryDivide and Conquer: A molecular tool kit to reprogram the biosynthesis of non-ribosomal peptides.

scholarly journals Type S Non Ribosomal Peptide Synthetases for the rapid generation of tailor-made peptide libraries

2021 ◽  
Author(s):  
Nadya Abbood ◽  
Tien Duy Vo ◽  
Jonas Watzel ◽  
Kenan A. J. Bozhueyuek ◽  
Helge B. Bode
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
De Novo ◽  
Chemical Space ◽  
Biologically Relevant ◽  
Peptide Synthetases ◽  
Medical Needs ◽  
Natural Product Research ◽  
Rapid Generation ◽  
Traditional Natural

Bacterial natural products in general, and non-ribosomally synthesized peptides in particular, are structurally diverse and provide us with a broad range of pharmaceutically relevant bioactivities. Yet, traditional natural product research suffers from rediscovering the same scaffolds and has been stigmatised as inefficient, time-, labour-, and cost-intensive. Combinatorial chemistry, on the other hand, can produce new molecules in greater numbers, cheaper and in less time than traditional natural product discovery, but also fails to meet current medical needs due to the limited biologically relevant chemical space that can be addressed. Consequently, methods for the high throughput generation of new-to-nature natural products would offer a new approach to identifying novel bioactive chemical entities for the hit to lead phase of drug discovery programms. As a follow-up to our previously published proof-of-principle study on generating bipartite type S non-ribosomal peptide synthetases (NRPSs), we now envisaged the de novo generation of non-ribosomal peptides (NRPs) on an unreached scale. Using synthetic zippers, we split NRPS in up to three subunits and rapidly generated different bi- and tripartite NRPS libraries to produce 49 peptides, peptide derivatives, and de novo peptides at good titres up to 145 mgL-1. A further advantage of type S NRPSs not only is the possibility to easily expand the created libraries by re-using previously created type S NRPS, but that functions of individual domains as well as domain-domain interactions can be studied and assigned rapidly.

scholarly journals Active site-directed proteomic probes for adenylation domains in nonribosomal peptide synthetases

2015 ◽  
Vol 51 (12) ◽  
pp. 2262-2265 ◽  
Author(s):  
Sho Konno ◽  
Fumihiro Ishikawa ◽  
Takehiro Suzuki ◽  
Naoshi Dohmae ◽  
Michael D. Burkart ◽  
...  
Keyword(s):  
Natural Product ◽  
Active Site ◽  
Nonribosomal Peptide Synthetase ◽  
Protein Labeling ◽  
Nonribosomal Peptide ◽  
Nonribosomal Peptide Synthetases ◽  
Peptide Synthetases ◽  
Peptide Synthetase ◽  
A Domains

Active site-directed proteomic probes coupled to the 5′-O-N-(aminoacyl)sulfamoyladenosine (AMS) scaffold with a clickable benzophenone functionality selectively target nonribosomal peptide synthetase (NRPS) adenylation (A) domains in natural product producer proteomes by ligand-directed protein labeling.

New chemistry from natural product biosynthesis

2016 ◽  
Vol 44 (3) ◽  
pp. 738-744 ◽  
Author(s):  
Catherine B. Hubert ◽  
Sarah M. Barry
Keyword(s):  
Natural Product ◽  
Chemical Reactions ◽  
Bond Activation ◽  
Synthetic Chemistry ◽  
Biosynthetic Pathways ◽  
Natural Product Biosynthesis ◽  
Bulk Chemicals ◽  
Enzyme Discovery ◽  
Starting Point ◽  
Product Assembly

Catalysts are a vital part of synthetic chemistry. However, there are still many important reactions for which catalysts have not been developed. The use of enzymes as biocatalysts for synthetic chemistry is growing in importance due to the drive towards sustainable methods for producing both bulk chemicals and high value compounds such as pharmaceuticals, and due to the ability of enzymes to catalyse chemical reactions with excellent stereoselectivity and regioselectivity. Such challenging transformations are a common feature of natural product biosynthetic pathways. In this mini-review, we discuss the potential to use biosynthetic pathways as a starting point for biocatalyst discovery. We introduce the reader to natural product assembly and tailoring, then focus on four classes of enzyme that catalyse C─H bond activation reactions to functionalize biosynthetic precursors. Finally, we briefly discuss the challenges involved in novel enzyme discovery.

Analysis of the Sorangicin Gene Cluster Reinforces the Utility of a Combined Phylogenetic/Retrobiosynthetic Analysis for Deciphering Natural Product Assembly by trans-AT PKS

ChemBioChem ◽  
2010 ◽  
Vol 11 (13) ◽  
pp. 1840-1849 ◽  
Author(s):  
Herbert Irschik ◽  
Maren Kopp ◽  
Kira J. Weissman ◽  
Kathrin Buntin ◽  
Jörn Piel ◽  
...  
Keyword(s):  
Natural Product ◽  
Gene Cluster ◽  
Product Assembly

scholarly journals Distribution and Diversity of Natural Product Genes in Marine and Freshwater Cyanobacterial Cultures and Genomes

2005 ◽  
Vol 71 (11) ◽  
pp. 7401-7413 ◽  
Author(s):  
Ian M. Ehrenreich ◽  
John B. Waterbury ◽  
Eric A. Webb
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Phylogenetic Analyses ◽  
Molecular Data ◽  
Degenerate Primers ◽  
Molecular Systems ◽  
Peptide Synthetases ◽  
Sequence Identification ◽  
Functionally Diverse ◽  
Novel Products

ABSTRACT Natural products are a functionally diverse class of biochemically synthesized compounds, which include antibiotics, toxins, and siderophores. In this paper, we describe both the detection of natural product activities and the sequence identification of gene fragments from two molecular systems that have previously been implicated in natural product production, i.e., nonribosomal peptide synthetases (NRPSs) and modular polyketide synthases (PKSs), in diverse marine and freshwater cyanobacterial cultures. Using degenerate PCR and the sequencing of cloned products, we show that NRPSs and PKSs are common among the cyanobacteria tested. Our molecular data, when combined with genomic searches of finished and progressing cyanobacterial genomes, demonstrate that not all cyanobacteria contain NRPS and PKS genes and that the filamentous and heterocystous cyanobacteria are the richest sources of these genes and the most likely sources of novel natural products within the phylum. In addition to validating the use of degenerate primers for the identification of PKS and NRPS genes in cyanobacteria, this study also defines numerous gene fragments that will be useful as probes for future studies of the synthesis of natural products in cyanobacteria. Phylogenetic analyses of the cyanobacterial NRPS and PKS fragments sequenced in this study, as well as those from the cyanobacterial genome projects, demonstrate that there is remarkable diversity and likely novelty of these genes within the cyanobacteria. These results underscore the potential variety of novel products being produced by these ubiquitous organisms.

scholarly journals Aflatoxin B1 Affects Kenyan Markets: How It Can be Managed

2020 ◽  
pp. 1-5
Author(s):  
Solomon Omwoma Lugasi
Keyword(s):  
Supply Chain ◽  
Natural Product ◽  
Aflatoxin B1 ◽  
Peanut Butter ◽  
Aflatoxin Contamination ◽  
Food Crops ◽  
Fungal Metabolites ◽  
Maize Flour ◽  
Food Supply Chain ◽  
Parent Companies

Aflatoxin B1 is a toxin produced as secondary fungal metabolites by the fungus Aspergillus, particularly A. flavus. The toxin has significantly contaminated the food supply chain especially cereals in Kenya. Kenya Bureau of Standards (KEBS) has recently banned five maize flour brands, citing high aflatoxin levels. They also suspended seven peanut butter products and the permits of their parent companies over aflatoxin contamination. The huge losses encountered by these companies calls for concerted efforts to manage aflatoxin in cereals. Aflasafe, a natural product for controlling poisonous A. flavus in food crops, including maize is made from roasted sterile sorghum (usually colored blue using food color) coated with non-poison producing types of A. flavus native to Kenya. The product is broadcasted in the maize fields during flowering and after exposure to sufficient moisture, the friendly Aflasafe fungi grow out as green spores containing millions of spores that are eventually spread to the crop, carried by wind and insects in the manner that aflatoxin-producing fungi are spread.

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