Structure, biosynthesis, and biological activities of cyclooligomer depsipeptides from fungi

Cyclooligomer depsipeptides (CODs) are peptolides, in which their symmetric structure ring structure has two or more ester bonds formed and alternately arranged between amino and α-hydroxy acid. CODs belong to four main groups of cyclotetrapeptides, cyclohexadepsipeptides, cyclooctadepsipeptides and diketomorpholines. These compounds have been mainly isolated from Acremonium, Aspergillus, Beauveria, Cordyceps, Fusarium, Isaria, Nigrospora, Peacilomyces, and Verticillium. The biosynthesis of CODs takes place outside the ribosome by giant multi-domain enzymes called nonribosomal peptide synthetases (NRPSs). Two different models about the formation of these depsipeptides were proposed. Fungal CODs are known to exhibit various biological activities, especially insecticidal, antitumoral, antimicrobial and antiviral activities. Therefore, CODs are considered to be natural substances with extremely potential applications in medicine and agriculture. This review highlights the structures, classification, biosynthesis, and biological activities of the fungal CODs.

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Optimizing dimodular nonribosomal peptide synthetases and natural dipeptides in an Escherichia coli heterologous host

Biochemistry and Cell Biology ◽

10.1139/bcb-2012-0097 ◽

2013 ◽

Vol 91 (4) ◽

pp. 203-208 ◽

Cited By ~ 7

Author(s):

Morgan A. Wyatt ◽

Nathan A. Magarvey

Keyword(s):

Escherichia Coli ◽

Biological Activities ◽

Structural Complexity ◽

Biosynthetic Gene Cluster ◽

Nonribosomal Peptides ◽

Heterologous Host ◽

T7 Promoter ◽

Nonribosomal Peptide ◽

Nonribosomal Peptide Synthetases ◽

Peptide Synthetases

Nonribosomal peptides are an important class of natural products that have a broad range of biological activities. Their structural complexity often prevents simple chemical synthesis, and production from the natural producer is often low, which deters pharmaceutical development. Expression of biosynthetic machinery in heterologous host organisms like Escherichia coli is one way to access these structures, and subsequent optimization of these systems is critical for future development. We utilized the aureusimine biosynthetic gene cluster as a model system to identify the optimal conditions to produce nonribosomal peptides in the isopropyl β-d-1-thiogalactopyranoside (IPTG)-inducible T7 promoter system of pET28. Single reaction monitoring of nonribosomal products was used to find the optimal concentration of IPTG, postinduction temperature, and the effect of amino acid precursor supplementation. In addition, principle component analysis of these extracts identified 3 previously undiscovered pyrazine products of the aureusimine biosynthetic locus, highlighting the utility of heterologously expressing nonribosomal peptide synthetases to find new products.

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Functional Analysis of All Nonribosomal Peptide Synthetases in Cochliobolus heterostrophus Reveals a Factor, NPS6, Involved in Virulence and Resistance to Oxidative Stress

Eukaryotic Cell ◽

10.1128/ec.4.3.545-555.2005 ◽

2005 ◽

Vol 4 (3) ◽

pp. 545-555 ◽

Cited By ~ 97

Author(s):

Bee-Na Lee ◽

Scott Kroken ◽

David Y. T. Chou ◽

Barbara Robbertse ◽

O. C. Yoder ◽

...

Keyword(s):

Oxidative Stress ◽

Polyketide Synthase ◽

Biological Activities ◽

Cochliobolus Heterostrophus ◽

Pcr Analysis ◽

Human Pathogens ◽

Fungal Virulence ◽

Nonribosomal Peptide ◽

Nonribosomal Peptide Synthetases ◽

Peptide Synthetases

ABSTRACT Nonribosomal peptides, made by nonribosomal peptide synthetases, have diverse biological activities, including roles as fungal virulence effectors. Inspection of the genome of Cochliobolus heterostrophus, a fungal pathogen of maize and a member of a genus noted for secondary metabolite production, revealed eight multimodular nonribosomal peptide synthase (NPS) genes and three monomodular NPS-like genes, one of which encodes a nonribosomal peptide synthetase/polyketide synthase hybrid enzyme presumed to be involved in synthesis of a peptide/polyketide molecule. Deletion of each NPS gene and phenotypic analyses showed that the product of only one of these genes, NPS6, is required for normal virulence on maize. NPS6 is also required for resistance to hydrogen peroxide, suggesting it may protect the fungus from oxidative stress. This and all other nps mutants had normal growth, mating ability, and appressoria. Real-time PCR analysis showed that expression of all NPS genes is low (relative to that of actin), that all (except possibly NPS2) are expressed during vegetative growth, and that expression is induced by nitrogen starvation. Only NPS6 is unfailingly conserved among euascomycete fungi, including plant and human pathogens and saprobes, suggesting the possibility that NPS6 activity provides oxidative stress protection during both saprobic and parasitic growth.

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