scholarly journals Sphinganine-Analog Mycotoxins (SAMs): Chemical Structures, Bioactivities, and Genetic Controls

2020 ◽  
Vol 6 (4) ◽  
pp. 312
Author(s):  
Jia Chen ◽  
Zhimin Li ◽  
Yi Cheng ◽  
Chunsheng Gao ◽  
Litao Guo ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Crop Production ◽  
Biological Activities ◽  
Structural Diversity ◽  
Pathogenic Fungi ◽  
Biosynthetic Gene Cluster ◽  
Sphingolipid Metabolism ◽  
Interspecific Difference ◽  
Sequence Comparisons ◽  
Chemical Structures

Sphinganine-analog mycotoxins (SAMs) including fumonisins and A. alternata f. sp. Lycopersici (AAL) toxins are a group of related mycotoxins produced by plant pathogenic fungi in the Fusarium genus and in Alternaria alternata f. sp. Lycopersici, respectively. SAMs have shown diverse cytotoxicity and phytotoxicity, causing adverse impacts on plants, animals, and humans, and are a destructive force to crop production worldwide. This review summarizes the structural diversity of SAMs and encapsulates the relationships between their structures and biological activities. The toxicity of SAMs on plants and animals is mainly attributed to their inhibitory activity against the ceramide biosynthesis enzyme, influencing the sphingolipid metabolism and causing programmed cell death. We also reviewed the detoxification methods against SAMs and how plants develop resistance to SAMs. Genetic and evolutionary analyses revealed that the FUM (fumonisins biosynthetic) gene cluster was responsible for fumonisin biosynthesis in Fusarium spp. Sequence comparisons among species within the genus Fusarium suggested that mutations and multiple horizontal gene transfers involving the FUM gene cluster were responsible for the interspecific difference in fumonisin synthesis. We finish by describing methods for monitoring and quantifying SAMs in food and agricultural products.

scholarly journals Discovery of the Pseudomonas Polyyne Protegencin by a Phylogeny-Guided Study of Polyyne Biosynthetic Gene Cluster Diversity

mBio ◽  
2021 ◽  
Author(s):  
Alex J. Mullins ◽  
Gordon Webster ◽  
Hak Joong Kim ◽  
Jinlian Zhao ◽  
Yoana D. Petrova ◽  
...  
Keyword(s):  
Biological Control ◽  
Natural Products ◽  
Gene Cluster ◽  
Plant Pathogens ◽  
Biological Activities ◽  
Pathogenic Fungi ◽  
Biosynthetic Gene Cluster ◽  
Biosynthetic Gene ◽  
Carbon Bond ◽  
Ecological Roles

Natural products bearing alkyne (triple carbon bond) or polyyne (multiple alternating single and triple carbon bonds) moieties exhibit a broad range of important biological activities. Polyyne metabolites have been implicated in important ecological roles such as cepacin mediating biological control of plant pathogens and caryoynencin protecting Lagriinae beetle eggs against pathogenic fungi.

scholarly journals Bioactive Molecules from Mangrove Streptomyces qinglanensis 172205

Marine Drugs ◽  
2020 ◽  
Vol 18 (5) ◽  
pp. 255
Author(s):  
Dongbo Xu ◽  
Erli Tian ◽  
Fandong Kong ◽  
Kui Hong
Keyword(s):  
Gene Cluster ◽  
Secondary Metabolite ◽  
Biosynthetic Gene Cluster ◽  
Bioactive Molecules ◽  
Spectroscopic Methods ◽  
Biosynthetic Gene ◽  
Electronic Circular Dichroism ◽  
Chemical Structures ◽  
New Compounds ◽  
Antiproliferative Activities

Five new compounds 15R-17,18-dehydroxantholipin (1), (3E,5E,7E)-3-methyldeca-3,5,7-triene-2,9-dione (2) and qinlactone A–C (3–5) were identified from mangrove Streptomyces qinglanensis 172205 with “genetic dereplication,” which deleted the highly expressed secondary metabolite-enterocin biosynthetic gene cluster. The chemical structures were established by spectroscopic methods, and the absolute configurations were determined by electronic circular dichroism (ECD). Compound 1 exhibited strong anti-microbial and antiproliferative bioactivities, while compounds 2–4 showed weak antiproliferative activities.

scholarly journals Natural Indole Alkaloids from Marine Fungi: Chemical Diversity and Biological Activities

2021 ◽  
Author(s):  
Jiao Li ◽  
Chun-Lin Zhuang
Keyword(s):  
Marine Fungi ◽  
Biological Activities ◽  
Indole Alkaloids ◽  
Structural Diversity ◽  
Heterocyclic Ring ◽  
Chemical Diversity ◽  
Pharmaceutical Development ◽  
Chemical Structures ◽  
Clinical Drugs ◽  
Unique Chemical

The indole scaffold is one of the most important heterocyclic ring systems for pharmaceutical development, and serves as an active moiety in several clinical drugs. Fungi derived from marine origin are more liable to produce novel indole-containing natural products due to their extreme living environments. The indole alkaloids from marine fungi have drawn considerable attention for their unique chemical structures and significant biological activities. This review attempts to provide a summary of the structural diversity of marine fungal indole alkaloids including prenylated indoles, diketopiperazine indoles, bisindoles or trisindoles, quinazoline-containing indoles, indole-diterpenoids, and other indoles, as well as their known biological activities, mainly focusing on cytotoxic, kinase inhibitory, antiinflammatory, antimicrobial, anti-insecticidal, and brine shrimp lethal effects. A total of 306 indole alkaloids from marine fungi have been summarized, covering the references published from 1995 to early 2021, expecting to be beneficial for drug discovery in the future.

scholarly journals Discovery, Bioactivity Evaluation, Biosynthetic Gene Cluster Identification, and Heterologous Expression of Novel Albofungin Derivatives

2021 ◽  
Vol 12 ◽  
Author(s):  
Weiyi She ◽  
Wenkang Ye ◽  
Aifang Cheng ◽  
Xin Liu ◽  
Jianwei Tang ◽  
...  
Keyword(s):  
Heterologous Expression ◽  
Gene Cluster ◽  
Pathogenic Bacteria ◽  
Streptomyces Coelicolor ◽  
Draft Genome ◽  
2D Nmr ◽  
Biosynthetic Gene Cluster ◽  
Open Reading Frames ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Chemical Structures

The crude extract of Streptomyces chrestomyceticus exhibited strong and broad activities against most “ESKAPE pathogens.” We conducted a comprehensive chemical investigation for secondary metabolites from the S. chrestomyceticus strain and identified two novel albofungin (alb) derivatives, i.e., albofungins A (1) and B (2), along with two known compounds, i.e., albofungin (3) and chloroalbofungin (4). The chemical structures of the novel compounds were elucidated using HRMS, 1D and 2D NMR, and electronic circular dichroism spectroscopy. The draft genome of S. chrestomyceticus was sequenced, and a 72 kb albofungin (alb) gene cluster with 72 open reading frames encoding type II polyketide synthases (PKSs), regulators, and transporters, and tailoring enzymes were identified using bioinformatics analysis. The alb gene cluster was confirmed using the heterologous expression in Streptomyces coelicolor, which successfully produced the compounds 3 and 4. Furthermore, compounds 1–4 displayed remarkable activities against Gram-positive bacteria and antitumor activities toward various cancer cells. Notably, compounds 1 and 3 showed potent activities against Gram-negative pathogenic bacteria. The terminal deoxynucleotidyl transferase (dUTP) nick-end labeling and flow cytometry analysis verified that compound 1 inhibited cancer cell proliferation by inducing cellular apoptosis. These results indicated that albofungins might be potential candidates for the development of antibiotics and antitumor drugs.

scholarly journals Superior production of heavy pamamycin derivatives using a bkdR deletion mutant of Streptomyces albus J1074/R2

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Lars Gläser ◽  
Martin Kuhl ◽  
Julian Stegmüller ◽  
Christian Rückert ◽  
Maksym Myronovskyi ◽  
...  
Keyword(s):  
Deletion Mutant ◽  
Biological Activities ◽  
Pathogenic Fungi ◽  
Nutrient Status ◽  
Building Blocks ◽  
Biosynthetic Gene Cluster ◽  
Efficient Production ◽  
Molecular Weights ◽  
Beneficial Effects ◽  
Coa Thioesters

Abstract Background Pamamycins are macrodiolides of polyketide origin which form a family of differently large homologues with molecular weights between 579 and 663. They offer promising biological activity against pathogenic fungi and gram-positive bacteria. Admittedly, production titers are very low, and pamamycins are typically formed as crude mixture of mainly smaller derivatives, leaving larger derivatives rather unexplored so far. Therefore, strategies that enable a more efficient production of pamamycins and provide increased fractions of the rare large derivatives are highly desired. Here we took a systems biology approach, integrating transcription profiling by RNA sequencing and intracellular metabolite analysis, to enhance pamamycin production in the heterologous host S. albus J1074/R2. Results Supplemented with l-valine, the recombinant producer S. albus J1074/R2 achieved a threefold increased pamamycin titer of 3.5 mg L−1 and elevated fractions of larger derivatives: Pam 649 was strongly increased, and Pam 663 was newly formed. These beneficial effects were driven by increased availability of intracellular CoA thioesters, the building blocks for the polyketide, resulting from l-valine catabolism. Unfavorably, l-valine impaired growth of the strain, repressed genes of mannitol uptake and glycolysis, and suppressed pamamycin formation, despite the biosynthetic gene cluster was transcriptionally activated, restricting production to the post l-valine phase. A deletion mutant of the transcriptional regulator bkdR, controlling a branched-chain amino acid dehydrogenase complex, revealed decoupled pamamycin biosynthesis. The regulator mutant accumulated the polyketide independent of the nutrient status. Supplemented with l-valine, the novel strain enabled the biosynthesis of pamamycin mixtures with up to 55% of the heavy derivatives Pam 635, Pam 649, and Pam 663: almost 20-fold more than the wild type. Conclusions Our findings open the door to provide rare heavy pamamycins at markedly increased efficiency and facilitate studies to assess their specific biological activities and explore this important polyketide further.

scholarly journals Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

2008 ◽  
Vol 190 (17) ◽  
pp. 6014-6025 ◽  
Author(s):  
Jie Fang ◽  
Yiping Zhang ◽  
Lijuan Huang ◽  
Xinying Jia ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Structural Diversity ◽  
Biosynthetic Gene Cluster ◽  
Combinatorial Biosynthesis ◽  
In Vitro Characterization ◽  
Fused Gene ◽  
Micromonospora Chalcea

ABSTRACT Tetrocarcin A (TCA), produced by Micromonospora chalcea NRRL 11289, is a spirotetronate antibiotic with potent antitumor activity and versatile modes of action. In this study, the biosynthetic gene cluster of TCA was cloned and localized to a 108-kb contiguous DNA region. In silico sequence analysis revealed 36 putative genes that constitute this cluster (including 11 for unusual sugar biosynthesis, 13 for aglycone formation, and 4 for glycosylations) and allowed us to propose the biosynthetic pathway of TCA. The formation of d-tetronitrose, l-amicetose, and l-digitoxose may begin with d-glucose-1-phosphate, share early enzymatic steps, and branch into different pathways by competitive actions of specific enzymes. Tetronolide biosynthesis involves the incorporation of a 3-C unit with a polyketide intermediate to form the characteristic spirotetronate moiety and trans-decalin system. Further substitution of tetronolide with five deoxysugars (one being a deoxynitrosugar) was likely due to the activities of four glycosyltransferases. In vitro characterization of the first enzymatic step by utilization of 1,3-biphosphoglycerate as the substrate and in vivo cross-complementation of the bifunctional fused gene tcaD3 (with the functions of chlD3 and chlD4) to ΔchlD3 and ΔchlD4 in chlorothricin biosynthesis supported the highly conserved tetronate biosynthetic strategy in the spirotetronate family. Deletion of a large DNA fragment encoding polyketide synthases resulted in a non-TCA-producing strain, providing a clear background for the identification of novel analogs. These findings provide insights into spirotetronate biosynthesis and demonstrate that combinatorial-biosynthesis methods can be applied to the TCA biosynthetic machinery to generate structural diversity.

scholarly journals Identification of a Biosynthetic Gene Cluster Responsible for the Production of a New Pyrrolopyrimidine Natural Product—Huimycin

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1074
Author(s):  
Hui Shuai ◽  
Maksym Myronovskyi ◽  
Suvd Nadmid ◽  
Andriy Luzhetskyy
Keyword(s):  
Gene Cluster ◽  
Gene Deletion ◽  
Biological Activities ◽  
Biosynthetic Gene Cluster ◽  
Resonance Spectroscopy ◽  
Important Class ◽  
Biosynthetic Gene ◽  
Heterologous Host ◽  
Streptomyces Albus ◽  
Actinomycete Strain

Pyrrolopyrimidines are an important class of natural products with a broad spectrum of biological activities, including antibacterial, antifungal, antiviral, anticancer or anti-inflammatory. Here, we present the identification of a biosynthetic gene cluster from the rare actinomycete strain Kutzneria albida DSM 43870, which leads to the production of huimycin, a new member of the pyrrolopyrimidine family of compounds. The huimycin gene cluster was successfully expressed in the heterologous host strain Streptomyces albus Del14. The compound was purified, and its structure was elucidated by means of nuclear magnetic resonance spectroscopy. The minimal huimycin gene cluster was identified through sequence analysis and a series of gene deletion experiments. A model for huimycin biosynthesis is also proposed in this paper.

scholarly journals Unusual Biosynthesis and Structure of Locillomycins from Bacillus subtilis 916

2015 ◽  
Vol 81 (19) ◽  
pp. 6601-6609 ◽  
Author(s):  
Chuping Luo ◽  
Xuehui Liu ◽  
Xian Zhou ◽  
Junyao Guo ◽  
John Truong ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Gene Cluster ◽  
Biosynthetic Gene Cluster ◽  
Content Type ◽  
Cyclic Lipopeptides ◽  
Chemical Structures ◽  
Molecular Features ◽  
Isolation And Characterization ◽  
Peptide Synthetase ◽  
Distinct Features

ABSTRACTThree families ofBacilluscyclic lipopeptides—surfactins, iturins, and fengycins—have well-recognized potential uses in biotechnology and biopharmaceutical applications. This study outlines the isolation and characterization of locillomycins, a novel family of cyclic lipopeptides produced byBacillus subtilis916. Elucidation of the locillomycin structure revealed several molecular features not observed in otherBacilluslipopeptides, including a unique nonapeptide sequence and macrocyclization. Locillomycins are active against bacteria and viruses. Biochemical analysis and gene deletion studies have supported the assignment of a 38-kb gene cluster as the locillomycin biosynthetic gene cluster. Interestingly, this gene cluster encodes 4 proteins (LocA, LocB, LocC, and LocD) that form a hexamodular nonribosomal peptide synthetase to biosynthesize cyclic nonapeptides. Genome analysis and the chemical structures of the end products indicated that the biosynthetic pathway exhibits two distinct features: (i) a nonlinear hexamodular assembly line, with three modules in the middle utilized twice and the first and last two modules used only once and (ii) several domains that are skipped or optionally selected.

scholarly journals Marine-Derived Macrocyclic Alkaloids (MDMAs): Chemical and Biological Diversity

Marine Drugs ◽  
2020 ◽  
Vol 18 (7) ◽  
pp. 368
Author(s):  
Hanan I. Althagbi ◽  
Walied M. Alarif ◽  
Khalid O. Al-Footy ◽  
Ahmed Abdel-Lateff
Keyword(s):  
Soft Tissue ◽  
Biological Diversity ◽  
Biological Activities ◽  
Structural Diversity ◽  
Pyridinium Salts ◽  
Chemical Structures ◽  
Ovarian Cancers ◽  
Potential Source ◽  
Structure Activity ◽  
Metastatic Soft Tissue Sarcoma

The curiosity and attention that researchers have devoted to alkaloids are due to their bioactivities, structural diversity, and intriguing chemistry. Marine-derived macrocyclic alkaloids (MDMAs) are considered to be a potential source of drugs. Trabectedin, a tetrahydroisoquinoline derivative, has been approved for the treatment of metastatic soft tissue sarcoma and ovarian cancers. MDMAs displayed potent activities that enabled them to be used as anticancer, anti-invasion, antimalarial, antiplasmodial, and antimicrobial. This review presents the reported chemical structures, biological activities, and structure–activity relationships of macrocyclic alkaloids from marine organisms that have been published since their discovery until May 2020. This includes 204 compounds that are categorized under eight subclasses: pyrroles, quinolines, bis-quinolizidines, bis-1-oxaquinolizidines, 3-alkylpiperidines, manzamines, 3-alkyl pyridinium salts, and motuporamines.

scholarly journals Study of bicyclomycin biosynthesis in Streptomyces cinnamoneus by genetic and biochemical approaches

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jerzy Witwinowski ◽  
Mireille Moutiez ◽  
Matthieu Coupet ◽  
Isabelle Correia ◽  
Pascal Belin ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Biological Activities ◽  
Large Family ◽  
Biosynthetic Gene Cluster ◽  
Biosynthetic Gene ◽  
Bacterial Transcription ◽  
Bicyclic Structure ◽  
Transcription Termination Factor

AbstractThe 2,5-Diketopiperazines (DKPs) constitute a large family of natural products with important biological activities. Bicyclomycin is a clinically-relevant DKP antibiotic that is the first and only member in a class known to target the bacterial transcription termination factor Rho. It derives from cyclo-(l-isoleucyl-l-leucyl) and has an unusual and highly oxidized bicyclic structure that is formed by an ether bridge between the hydroxylated terminal carbon atom of the isoleucine lateral chain and the alpha carbon of the leucine in the diketopiperazine ring. Here, we paired in vivo and in vitro studies to complete the characterization of the bicyclomycin biosynthetic gene cluster. The construction of in-frame deletion mutants in the biosynthetic gene cluster allowed for the accumulation and identification of biosynthetic intermediates. The identity of the intermediates, which were reproduced in vitro using purified enzymes, allowed us to characterize the pathway and corroborate previous reports. Finally, we show that the putative antibiotic transporter was dispensable for the producing strain.

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