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Fungal cryptic gene cluster

Johanna Mattay, Stefanie Houwaart, Wolfgang Hüttel
Echinocandins are antifungal nonribosomal hexapeptides produced by fungi. Two of the amino acids are hydroxy-l-prolines: trans -4-hydroxy-l-proline and, in most echinocandin structures, ( trans -2,3)-3-hydroxy-( trans -2,4)-4-methyl-l-proline. In the case of echinocandin biosynthesis by Glarea lozoyensis , both amino acids are found in pneumocandin A0 , while in pneumocandin B0 the latter residue is replaced by trans -3-hydroxy-l-proline (3-Hyp). We have recently reported that all three amino acids are generated by the 2-oxoglutarate-dependent proline hydroxylase GloF...
April 1, 2018: Applied and Environmental Microbiology
Saima Khalid, Joshua A Baccile, Joseph E Spraker, Joanna Tannous, Muhammad Imran, Frank C Schroeder, Nancy P Keller
Bacterial-fungal interactions are presumed to be mediated chiefly by small-molecule signals; however, little is known about the signaling networks that regulate antagonistic relationships between pathogens. Here, we show that the ralstonins, lipopeptides produced by the plant pathogenic bacteria Ralstonia solanacearum, interfere with germination of the plant-pathogenic fungus Aspergillus flavus by down-regulating expression of a cryptic biosynthetic gene cluster (BGC), named imq. Comparative metabolomic analysis of overexpression strains of the transcription factor ImqK revealed imq-dependent production of a family of tripeptide-derived alkaloids, the imizoquins...
January 19, 2018: ACS Chemical Biology
Tabea Schuetze, Vera Meyer
BACKGROUND: Genome mining approaches predict dozens of biosynthetic gene clusters in each of the filamentous fungal genomes sequenced so far. However, the majority of these gene clusters still remain cryptic because they are not expressed in their natural host. Simultaneous expression of all genes belonging to a biosynthetic pathway in a heterologous host is one approach to activate biosynthetic gene clusters and to screen the metabolites produced for bioactivities. Polycistronic expression of all pathway genes under control of a single and tunable promoter would be the method of choice, as this does not only simplify cloning procedures, but also offers control on timing and strength of expression...
September 25, 2017: Microbial Cell Factories
Jennifer Wakefield, Hossam M Hassan, Marcel Jaspars, Rainer Ebel, Mostafa E Rateb
The frequent re-isolation of known compounds is one of the major challenges in drug discovery. Many biosynthetic genes are not expressed under standard culture conditions, thus limiting the chemical diversity of microbial compounds that can be obtained through fermentation. On the other hand, the competition during co-cultivation of two or more different microorganisms in most cases leads to an enhanced production of constitutively present compounds or an accumulation of cryptic compounds that are not detected in axenic cultures of the producing strain under different fermentation conditions...
2017: Frontiers in Microbiology
Alexander J Carrillo, Patrick Schacht, Ilva E Cabrera, Johnathon Blahut, Loren Prudhomme, Sarah Dietrich, Thomas Bekman, Jennifer Mei, Cristian Carrera, Vivian Chen, Isaiah Clark, Gerardo Fierro, Logan Ganzen, Jose Orellana, Shelby Wise, Kevin Yang, Hui Zhong, Katherine A Borkovich
Regulation of gene expression by DNA-binding transcription factors is essential for proper control of growth and development in all organisms. In this study, we annotate and characterize growth and developmental phenotypes for transcription factor genes in the model filamentous fungus Neurospora crassa We identified 312 transcription factor genes, corresponding to 3.2% of the protein coding genes in the genome. The largest class was the fungal-specific Zn2Cys6 (C6) binuclear cluster, with 135 members, followed by the highly conserved C2H2 zinc finger group, with 61 genes...
September 7, 2017: G3: Genes—Genomes—Genetics
I Kutay Ozturk, Pranav Chettri, Pierre-Yves Dupont, Irene Barnes, Rebecca L McDougal, Geromy G Moore, Andre Sim, Rosie E Bradshaw
Fungal secondary metabolites have many important biological roles and some, like the toxic polyketide aflatoxin, have been intensively studied at the genetic level. Complete sets of polyketide synthase (PKS) genes can now be identified in fungal pathogens by whole genome sequencing and studied in order to predict the biosynthetic potential of those fungi. The pine needle pathogen Dothistroma septosporum is predicted to have only three functional PKS genes, a small number for a hemibiotrophic fungus. One of these genes is required for production of dothistromin, a polyketide virulence factor related to aflatoxin, whose biosynthetic genes are dispersed across one chromosome rather than being clustered...
July 6, 2017: Fungal Genetics and Biology: FG & B
Kenneth D Clevenger, Jin Woo Bok, Rosa Ye, Galen P Miley, Maria H Verdan, Thomas Velk, Cynthia Chen, KaHoua Yang, Matthew T Robey, Peng Gao, Matthew Lamprecht, Paul M Thomas, Md Nurul Islam, Jonathan M Palmer, Chengcang C Wu, Nancy P Keller, Neil L Kelleher
The genomes of filamentous fungi contain up to 90 biosynthetic gene clusters (BGCs) encoding diverse secondary metabolites-an enormous reservoir of untapped chemical potential. However, the recalcitrant genetics, cryptic expression, and unculturability of these fungi prevent scientists from systematically exploiting these gene clusters and harvesting their products. As heterologous expression of fungal BGCs is largely limited to the expression of single or partial clusters, we established a scalable process for the expression of large numbers of full-length gene clusters, called FAC-MS...
August 2017: Nature Chemical Biology
Peng Zhang, Xiuna Wang, Aili Fan, Yanjing Zheng, Xingzhong Liu, Shihua Wang, Huixi Zou, Berl R Oakley, Nancy P Keller, Wen-Bing Yin
Spore pigmentation is very common in the fungal kingdom. The best studied pigment in fungi is melanin which coats the surface of single cell spores. What and how pigments function in a fungal species with multiple cell conidia is poorly understood. Here, we identified and deleted a polyketide synthase (PKS) gene PfmaE and showed that it is essential for multicellular conidial pigmentation and development in a plant endophytic fungus, Pestalotiopsis fici. To further characterize the melanin pathway, we utilized an advanced Aspergillus nidulans heterologous system for the expression of the PKS PfmaE and the Pfma gene cluster...
August 2017: Molecular Microbiology
Ashraf S A El-Sayed, Salah E Abdel-Ghany, Gul Shad Ali
Filamentous fungi are prolific repertoire of structurally diverse secondary metabolites of remarkable biological activities such as lovastatin and paclitaxel that have been approved by FDA as drugs for hypercholesterolemia and cancer treatment. The clusters of genes encoding lovastatin and paclitaxel are cryptic at standard laboratory cultural conditions (Kennedy et al. Science 284:1368-1372, 1999; Bergmann et al. Nature Chem Biol 3:213-217, 2007). The expression of these genes might be triggered in response to nutritional and physical conditions; nevertheless, the overall yield of these metabolites does not match the global need...
May 2017: Applied Microbiology and Biotechnology
David J Newman
In this short review, I am discussing the relatively recent awareness of the role of symbionts in plant, marine-invertebrates and fungal areas. It is now quite obvious that in marine-invertebrates, a majority of compounds found are from either as yet unculturable or poorly culturable microbes, and techniques involving "state of the art" genomic analyses and subsequent computerized analyses are required to investigate these interactions. In the plant kingdom evidence is amassing that endophytes (mainly fungal in nature) are heavily involved in secondary metabolite production and that mimicking the microbial interactions of fermentable microbes leads to involvement of previously unrecognized gene clusters (cryptic clusters is one name used), that when activated, produce previously unknown bioactive molecules...
2016: Frontiers in Microbiology
Pranatchareeya Chankhamjon, Yuta Tsunematsu, Mie Ishida-Ito, Yuzuka Sasa, Florian Meyer, Daniela Boettger-Schmidt, Barbara Urbansky, Klaus-Dieter Menzel, Kirstin Scherlach, Kenji Watanabe, Christian Hertweck
The regioselective functionalization of non-activated carbon atoms such as aliphatic halogenation is a major synthetic challenge. A novel multifunctional enzyme catalyzing the geminal dichlorination of a methyl group was discovered in Aspergillus oryzae (Koji mold), an important fungus that is widely used for Asian food fermentation. A biosynthetic pathway encoded on two different chromosomes yields mono- and dichlorinated polyketides (diaporthin derivatives), including the cytotoxic dichlorodiaporthin as the main product...
September 19, 2016: Angewandte Chemie
Lena Studt, Sarah M Rösler, Immo Burkhardt, Birgit Arndt, Michael Freitag, Hans-Ulrich Humpf, Jeroen S Dickschat, Bettina Tudzynski
Filamentous fungi produce a vast array of secondary metabolites (SMs) and some play a role in agriculture or pharmacology. Sequencing of the rice pathogen Fusarium fujikuroi revealed the presence of far more SM-encoding genes than known products. SM production is energy-consuming and thus tightly regulated, leaving the majority of SM gene clusters silent under laboratory conditions. One important regulatory layer in SM biosynthesis involves histone modifications that render the underlying genes either silent or poised for transcription...
November 2016: Environmental Microbiology
Hsu-Hua Yeh, Manmeet Ahuja, Yi-Ming Chiang, C Elizabeth Oakley, Shauna Moore, Olivia Yoon, Heather Hajovsky, Jin-Woo Bok, Nancy P Keller, Clay C C Wang, Berl R Oakley
Fungal genome projects are revealing thousands of cryptic secondary metabolism (SM) biosynthetic gene clusters that encode pathways that potentially produce valuable compounds. Heterologous expression systems should allow these clusters to be expressed and their products obtained, but approaches are needed to identify the most valuable target clusters. The inp cluster of Aspergillus nidulans contains a gene, inpE, that encodes a proteasome subunit, leading us to hypothesize that the inp cluster produces a proteasome inhibitor and inpE confers resistance to this compound...
August 19, 2016: ACS Chemical Biology
Chi-Ching Tsang, Jasper F W Chan, Wai-Mei Pong, Jonathan H K Chen, Antonio H Y Ngan, Mei Cheung, Christopher K C Lai, Dominic N C Tsang, Susanna K P Lau, Patrick C Y Woo
"Engyodontium album" is an environmental saprobic mould and an emerging opportunistic pathogen able to cause both superficial and systemic infections. In this study, we isolated a mould from the skin lesion biopsy specimen of the right shin in a patient who received renal transplantation for end-stage renal failure with prednisolone, tacrolimus, and azathioprine immunosuppressant therapy. Histology of the skin biopsy showed mild squamous hyperplasia and neutrophilic infiltrate in the epidermis, active chronic inflammation in the dermis, and fat necrosis in the subcutis, with numerous fungal elements within the serum crusts...
October 1, 2016: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Koji Narita, Ryota Chiba, Atsushi Minami, Motoichiro Kodama, Isao Fujii, Katsuya Gomi, Hideaki Oikawa
Heterologous expression of four candidate genes found in ophiobolin gene clusters from three fungal strains was employed to elucidate the late-stage biosynthetic pathway of phytotoxin ophiobolin. Expression of oblBAc (cytochrome P450) from the cryptic gene cluster gave unexpected products, and that of oblBBm/oblBEv from the gene cluster of ophiobolin producers, with oblDBm as the transporter, yielded intermediate ophiobolin C through an unusual four-step oxidation process. The observation made in this study may provide a useful guideline for the elucidation of genuine biosynthetic pathways of natural products...
May 6, 2016: Organic Letters
Alexandra A Soukup, Nancy P Keller, Philipp Wiemann
Filamentous fungi are historically known as rich sources for production of biologically active natural products, so-called secondary metabolites. One particularly pharmaceutically relevant chemical group of secondary metabolites is the nonribosomal peptides synthesized by nonribosomal peptide synthetases (NRPSs). As most of the fungal NRPS gene clusters leading to production of the desired molecules are not expressed under laboratory conditions, efforts to overcome this impediment are crucial to unlock the full chemical potential of each fungal species...
2016: Methods in Molecular Biology
Scott Griffiths, Benedetta Saccomanno, Pierre J G M de Wit, Jérôme Collemare
Cladosporium fulvum is a non-obligate biotrophic fungal tomato pathogen for which fifteen secondary metabolite (SM) gene clusters were previously identified in its genome. However, most of these SM biosynthetic pathways remain cryptic during growth in planta and in different in vitro conditions. The sole SM produced in vitro is the pigment cladofulvin. In this study, we attempted to activate cryptic pathways in order to identify new compounds produced by C. fulvum. For this purpose, we manipulated orthologues of the global regulators VeA, LaeA and HdaA known to regulate SM biosynthesis in other fungal species...
November 2015: Fungal Genetics and Biology: FG & B
Daniel Montiel, Hahk-Soo Kang, Fang-Yuan Chang, Zachary Charlop-Powers, Sean F Brady
Large-scale sequencing of prokaryotic (meta)genomic DNA suggests that most bacterial natural product gene clusters are not expressed under common laboratory culture conditions. Silent gene clusters represent a promising resource for natural product discovery and the development of a new generation of therapeutics. Unfortunately, the characterization of molecules encoded by these clusters is hampered owing to our inability to express these gene clusters in the laboratory. To address this bottleneck, we have developed a promoter-engineering platform to transcriptionally activate silent gene clusters in a model heterologous host...
July 21, 2015: Proceedings of the National Academy of Sciences of the United States of America
Kristian F Nielsen, Thomas O Larsen
Having entered the Genomic Era, it is now evident that the biosynthetic potential of filamentous fungi is much larger than was thought even a decade ago. Fungi harbor many cryptic gene clusters encoding for the biosynthesis of polyketides, non-ribosomal peptides, and terpenoids - which can all undergo extensive modifications by tailoring enzymes - thus potentially providing a large array of products from a single pathway. Elucidating the full chemical profile of a fungal species is a challenging exercise, even with elemental composition provided by high-resolution mass spectrometry (HRMS) used in combination with chemical databases (e...
2015: Frontiers in Microbiology
Sylvie Pažoutová, Kamila Pešicová, Milada Chudíčková, Petr Šrůtka, Miroslav Kolařík
Claviceps purpurea is an ovarian parasite infecting grasses (Poaceae) including cereals and forage plants. This fungus produces toxic alkaloids and consumption of contaminated grains can cause ergotism in humans and other mammals. Recent molecular genetics studies have indicated that it included three cryptic species (G1, G2, G3). In this study, reproductive isolation amongst these groups and among material from Phragmites and Molinia was tested using gene flow statistics for five polymorphic loci, and to support these data, phylogenetic affiliations based on gene trees and a multigene phylogeny were used...
January 2015: Fungal Biology
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