Academic literature on the topic 'Fungal Folate Pathway'
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Journal articles on the topic "Fungal Folate Pathway"
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Luraschi, A., O. H. Cissé, M. Monod, M. Pagni, and P. M. Hauser. "Functional Characterization of the Pneumocystis jirovecii Potential Drug Targetsdhfsandabz2Involved in Folate Biosynthesis." Antimicrobial Agents and Chemotherapy 59, no. 5 (February 17, 2015): 2560–66. http://dx.doi.org/10.1128/aac.05092-14.
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ABSTRACTPneumocystisspecies are fungal parasites colonizing mammal lungs with strict host specificity.Pneumocystis jiroveciiis the human-specific species and can turn into an opportunistic pathogen causing severe pneumonia in immunocompromised individuals. This disease is currently the second most frequent life-threatening invasive fungal infection worldwide. The most efficient drug, cotrimoxazole, presents serious side effects, and resistance to this drug is emerging. The search for new targets for the development of new drugs is thus of utmost importance. The recent release of theP. jiroveciigenome sequence opens a new era for this task. It can now be carried out on the actual targets to be inhibited instead of on those of the relatively distant modelPneumocystis carinii, the species infecting rats. We focused on the folic acid biosynthesis pathway because (i) it is widely used for efficient therapeutic intervention, and (ii) it involves several enzymes that are essential for the pathogen and have no human counterparts. In this study, we report the identification of two such potential targets within the genome ofP. jirovecii, the dihydrofolate synthase (dhfs) and the aminodeoxychorismate lyase (abz2). The function of these enzymes was demonstrated by the rescue of the null allele of the orthologous gene ofSaccharomyces cerevisiae.
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Stogios, Peter J., Sean D. Liston, Cameron Semper, Bradley Quade, Karolina Michalska, Elena Evdokimova, Shane Ram, et al. "Molecular analysis and essentiality of Aro1 shikimate biosynthesis multi-enzyme in Candida albicans." Life Science Alliance 5, no. 8 (May 5, 2022): e202101358. http://dx.doi.org/10.26508/lsa.202101358.
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In the human fungal pathogen Candida albicans, ARO1 encodes an essential multi-enzyme that catalyses consecutive steps in the shikimate pathway for biosynthesis of chorismate, a precursor to folate and the aromatic amino acids. We obtained the first molecular image of C. albicans Aro1 that reveals the architecture of all five enzymatic domains and their arrangement in the context of the full-length protein. Aro1 forms a flexible dimer allowing relative autonomy of enzymatic function of the individual domains. Our activity and in cellulo data suggest that only four of Aro1’s enzymatic domains are functional and essential for viability of C. albicans, whereas the 3-dehydroquinate dehydratase (DHQase) domain is inactive because of active site substitutions. We further demonstrate that in C. albicans, the type II DHQase Dqd1 can compensate for the inactive DHQase domain of Aro1, suggesting an unrecognized essential role for this enzyme in shikimate biosynthesis. In contrast, in Candida glabrata and Candida parapsilosis, which do not encode a Dqd1 homolog, Aro1 DHQase domains are enzymatically active, highlighting diversity across Candida species.
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Ren, Xiyi, Yongxiang Liu, Yumei Tan, Yonghui Huang, Zuoyi Liu, and Xuanli Jiang. "Sequencing and Functional Annotation of the Whole Genome of Shiraia bambusicola." G3: Genes|Genomes|Genetics 10, no. 1 (November 11, 2019): 23–35. http://dx.doi.org/10.1534/g3.119.400694.
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Shiraia bambusicola is a rare medicinal fungus found in China that causes bamboo plants to decay and die with severe infection. Hypocrellin, its main active ingredient, is widely used in several fields, such as medicine, agriculture, and food industry. In this study, to clarify the genomic components, taxonomic status, pathogenic genes, secondary metabolite synthesis pathways, and regulatory mechanisms of S. bambusicola, whole-genome sequencing, assembly, and functional annotation were performed using high-throughput sequencing and bioinformatics approaches. It was observed that S. bambusicola has 33 Mb genome size, 48.89% GC content, 333 scaffolds, 2590 contigs, 10,703 genes, 82 tRNAs, and 21 rRNAs. The total length of the repeat sequence is 2,151,640 bp. The annotation of 5945 proteins was obtained from InterProScan hits based on the Gene Ontology database. Phylogenetic analysis showed that S. bambusicola belongs to Shiraiaceae, a new family of Pleosporales. It was speculated that there are more than two species or genus in Shiraiaceae. According to the annotation, 777 secreted proteins were associated with virulence or detoxification, including 777 predicted by the PHI database, 776 by the CAZY and Fungal CytochromeP450 database, and 441 by the Proteases database. The 252 genes associated with the secondary metabolism of S. bambusicola were screened and enriched into 28 pathways, among which the terpenoids, staurosporine, aflatoxin, and folate synthesis pathways have not been reported in S. bambusicola. The T1PKS was the main gene cluster among the 28 secondary metabolite synthesis gene clusters in S. bambusicola. The analysis of the T3PKS gene cluster related to the synthesis of hypocrellin showed that there was some similarity between S. bambusicola and 10 other species of fungi; however, the similarity was very low wherein the highest similarity was 17%. The genomic information of S. bambusicola obtained in this study was valuable to understand its genetic function and pathogenicity. The genomic information revealed that several enzyme genes and secreted proteins might be related to their host interactions and pathogenicity. The annotation and analysis of its secondary metabolite synthesis genes and gene clusters will be an important reference for future studies on the biosynthesis and regulation mechanism of the secondary metabolites, contributing to the discovery of new metabolites and accelerating drug development and application.
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DeJarnette, Christian, Arturo Luna-Tapia, Leanna R. Estredge, and Glen E. Palmer. "Dihydrofolate Reductase Is a Valid Target for Antifungal Development in the Human Pathogen Candida albicans." mSphere 5, no. 3 (June 24, 2020). http://dx.doi.org/10.1128/msphere.00374-20.
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ABSTRACT While the folate biosynthetic pathway has provided a rich source of antibacterial, antiprotozoal, and anticancer therapies, it has not yet been exploited to develop uniquely antifungal agents. Although there have been attempts to develop fungal-specific inhibitors of dihydrofolate reductase (DHFR), the protein itself has not been unequivocally validated as essential for fungal growth or virulence. The purpose of this study was to establish dihydrofolate reductase as a valid antifungal target. Using a strain with doxycycline-repressible transcription of DFR1 (PTETO-DFR1 strain), we were able to demonstrate that Dfr1p is essential for growth in vitro. Furthermore, nutritional supplements of most forms of folate are not sufficient to restore growth when Dfr1p expression is suppressed or when its activity is directly inhibited by methotrexate, indicating that Candida albicans has a limited capacity to acquire or utilize exogenous sources of folate. Finally, the PTETO-DFR1 strain was rendered avirulent in a mouse model of disseminated candidiasis upon doxycycline treatment. Collectively, these results confirm the validity of targeting dihydrofolate reductase and, by inference, other enzymes in the folate biosynthetic pathway as a strategy to devise new and efficacious therapies to combat life-threatening invasive fungal infections. IMPORTANCE The folate biosynthetic pathway is a promising and understudied source for novel antifungals. Even dihydrofolate reductase (DHFR), a well-characterized and historically important drug target, has not been conclusively validated as an antifungal target. Here, we demonstrate that repression of DHFR inhibits growth of Candida albicans, a major human fungal pathogen. Methotrexate, an antifolate, also inhibits growth but through pH-dependent activity. In addition, we show that C. albicans has a limited ability to take up or utilize exogenous folates as only the addition of high concentrations of folinic acid restored growth in the presence of methotrexate. Finally, we show that repression of DHFR in a mouse model of infection was sufficient to eliminate host mortality. Our work conclusively establishes DHFR as a valid antifungal target in C. albicans.
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Zhang, Bo, Yu Chen, Sheng-Xian Jiang, Xue Cai, Kai Huang, Zhi-Qiang Liu, and Yu-Guo Zheng. "Comparative metabolomics analysis of amphotericin B high-yield mechanism for metabolic engineering." Microbial Cell Factories 20, no. 1 (March 9, 2021). http://dx.doi.org/10.1186/s12934-021-01552-z.
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Abstract Background The polyene macrocyclic compound amphotericin B (AmB) is an important antifungal antibiotic for the clinical treatment of invasive fungal infections. To rationally guide the improvement of AmB production in the main producing strain Streptomyces nodosus, comparative metabolomics analysis was performed to investigate the intracellular metabolic changes in wild-type S. nodosus ZJB20140315 with low-yield AmB production and mutant S. nodosus ZJB2016050 with high-yield AmB production, the latter of which reached industrial criteria on a pilot scale. Results To investigate the relationship of intracellular metabolites, 7758 metabolites were identified in mutant S. nodosus and wildtype S. nodosus via LC–MS. Through analysis of metabolism, the level of 26 key metabolites that involved in carbon metabolism, fatty acids metabolism, amino acids metabolism, purine metabolism, folate biosynthesis and one carbon pool by folate were much higher in mutant S. nodosus. The enrichment of relevant metabolic pathways by gene overexpression strategy confirmed that one carbon pool by folate was the key metabolic pathway. Meanwhile, a recombinant strain with gene metH (methionine synthase) overexpressed showed 5.03 g/L AmB production within 120 h fermentation, which is 26.4% higher than that of the mutant strain. Conclusions These results demonstrated that comparative metabolomics analysis was an effective approach for the improvement of AmB production and could be applied for other industrially or clinically important compounds as well.
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Basak, Trambak, Virendra Nath, Vipin Kumar, and Amit Kumar Goyal. "In Silico Identification of Antifungal Compounds as Mutant DHFRase Inhibitors: Structure-based Approach, Molecular Dynamics Simulation and Structural Integrity Analysis." Journal of Computational Biophysics and Chemistry, August 28, 2021, 2150034. http://dx.doi.org/10.1142/s2737416521500344.
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Fungal infection of invasive nature is an alarming threat globally and a leading cause of human morbidity and mortality as they are opportunistic in nature. Rising resistance to current clinically approved marketed products for fungal infections is a major concern for humans. Dihydrofolate Reductase (DHFRase) is an essential enzyme in folate metabolic pathway responsible for DNA synthesis and is ubiquitous to all organisms, and also acts as a key target for developing antifungal drugs. In this study, potential mutant DHFRase inhibitors were screened with the help of hierarchical mode of docking of virtual library of antifungal compounds and molecular dynamic (MD) simulation. The identification of best hits was done by using the docking, binding energy prediction and further, which was supported by their predicted pharmacokinetics. MD simulation of the human DHFRase enzyme with the reference lead compound i.e. PY957 and most promising hit found i.e. ChemDiv-C390-0455 and to validate the stability of enzyme-ligand complex in best 07 retrieved hit as a potential mutant DHFRase inhibitor. The key residues Glh30, Phe34, Phe64, Phe31 of the binding pocket acknowledged as essential were found to be matching with the key interactions of the selected hit. Computed root mean square deviation (RMSD) and root mean square fluctuation (RMSF) in MD simulation of complex of DHFRase enzyme with PY957 and ChemDiv-C390-0455 were read less than 2.25[Formula: see text]Å during 100 nanoseconds simulation for both complex.
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Dai, Yuan-feng, Xiao-mao Wu, Han-cheng Wang, Wen-hong Li, Liu-ti Cai, Ji-xin Li, Feng Wang, Shafaque Sehar, and Imran Haider Shamsi. "Spatio-Temporal Variation in the Phyllospheric Microbial Biodiversity of Alternaria Alternata-Infected Tobacco Foliage." Frontiers in Microbiology 13 (July 28, 2022). http://dx.doi.org/10.3389/fmicb.2022.920109.
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Phyllospheric microbial composition of tobacco (Nicotiana tabacum L.) is contingent upon certain factors, such as the growth stage of the plant, leaf position, and cultivar and its geographical location, which influence, either directly or indirectly, the growth, overall health, and production of the tobacco plant. To better understand the spatiotemporal variation of the community and the divergence of phyllospheric microflora, procured from healthy and diseased tobacco leaves infected by Alternaria alternata, the current study employed microbe culturing, high-throughput technique, and BIOLOG ECO. Microbe culturing resulted in the isolation of 153 culturable fungal isolates belonging to 33 genera and 99 bacterial isolates belonging to 15 genera. High-throughput sequencing revealed that the phyllosphere of tobacco was dominantly colonized by Ascomycota and Proteobacteria, whereas, the most abundant fungal and bacterial genera were Alternaria and Pseudomonas. The relative abundance of Alternaria increased in the upper and middle healthy groups from the first collection time to the third, whereas, the relative abundance of Pseudomonas, Sphingomonas, and Methylobacterium from the same positions increased during gradual leaf aging. Non-metric multi-dimensional scaling (NMDs) showed clustering of fungal communities in healthy samples, while bacterial communities of all diseased and healthy groups were found scattered. FUNGuild analysis, from the first collection stage to the third one in both groups, indicated an increase in the relative abundance of Pathotroph-Saprotroph, Pathotroph-Saprotroph-Symbiotroph, and Pathotroph-Symbiotroph. Inclusive of all samples, as per the PICRUSt analysis, the predominant pathway was metabolism function accounting for 50.03%. The average values of omnilog units (OUs) showed relatively higher utilization rates of carbon sources by the microbial flora of healthy leaves. According to the analysis of genus abundances, leaf growth and leaf position were the important drivers of change in structuring the microbial communities. The current findings revealed the complex ecological dynamics that occur in the phyllospheric microbial communities over the course of a spatiotemporal varying environment with the development of tobacco brown spots, highlighting the importance of community succession.
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Kännaste, Astrid, Liina Jürisoo, Eve Runno-Paurson, Eero Talts, Rein Drenkhan, and Ülo Niinemets. "Impacts of Dutch elm disease-causing fungi on foliage photosynthetic characteristics and volatiles in Ulmus species with different pathogen resistance." Tree Physiology, September 15, 2022. http://dx.doi.org/10.1093/treephys/tpac108.
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Abstract Global warming affects the abiotic and biotic growth environment of plants, including the spread of fungal diseases such as Dutch elm disease (DED). DED-resistance of different Ulmus species varies, but how this is reflected in leaf-level physiological pathogen responses has not been investigated. We studied the impacts of mechanical injury alone and mechanical injury plus inoculation with the DED-causing pathogens Ophiostoma novo-ulmi subsp. novo-ulmi and O. novo-ulmi subsp. americana on Ulmus glabra, a more vulnerable species, and U. laevis, a more resistant species. Plant stress responses were evaluated for 12 days after stress application by monitoring leaf net CO2 assimilation rate (A), stomatal conductance (gs), ratio of ambient to intercellular CO2 concentration (Ca/Ci), intrinsic water use efficiency (iWUE, A/gs) and by measuring biogenic volatile (VOC) release by plant leaves. In U. glabra and U. laevis, A was not affected by time, stressors or their interaction. Only in U. glabra gs and Ca/Ci decreased in time, yet recovered by the end of the experiment. Although the emission compositions were affected in both species, the stress treatments enhanced VOC emission rates only in U. laevis. In this species, mechanical injury especially when combined to the pathogens increased the emission of lipoxygenase (LOX) pathway volatiles and dimethylallyl diphosphate and geranyl diphosphate (DMADP and GDP) pathway volatiles. In conclusion, the more resistant species U. laevis had a more stable photosynthesis, but stronger pathogen-elicited volatile response, especially after inoculation by O. novo-ulmi subsp. novo-ulmi. Thus, stronger activation of defenses might underlay higher DED-resistance in this species.
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Katsoula, A., S. Vasileiadis, M. Sapountzi, and Dimitrios G. Karpouzas. "The response of soil and phyllosphere microbial communities to repeated application of the fungicide iprodione: accelerated biodegradation or toxicity?" FEMS Microbiology Ecology 96, no. 6 (March 28, 2020). http://dx.doi.org/10.1093/femsec/fiaa056.
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ABSTRACT Pesticides interact with microorganisms in various ways with the outcome being negative or positive for the soil microbiota. Pesticides' effects on soil microorganisms have been studied extensively in soil but not in other pesticides-exposed microbial habitats like the phyllosphere. We tested the hypothesis that soil and phyllosphere support distinct microbial communities, but exhibit a similar response (accelerated biodegradation or toxicity) to repeated exposure to the fungicide iprodione. Pepper plants received four repeated foliage or soil applications of iprodione, which accelerated its degradation in soil (DT50_1st = 1.23 and DT50_4th = 0.48 days) and on plant leaves (DT50_1st > 365 and DT50_4th = 5.95 days). The composition of the epiphytic and soil bacterial and fungal communities, determined by amplicon sequencing, was significantly altered by iprodione. The archaeal epiphytic and soil communities responded differently; the former showed no response to iprodione. Three iprodione-degrading Paenarthrobacter strains were isolated from soil and phyllosphere. They hydrolyzed iprodione to 3,5-dichloraniline via the formation of 3,5-dichlorophenyl-carboxiamide and 3,5-dichlorophenylurea-acetate, a pathway shared by other soil-derived arthrobacters implying a phylogenetic specialization in iprodione biotransformation. Our results suggest that iprodione-repeated application could affect soil and epiphytic microbial communities with implications for the homeostasis of the plant–soil system and agricultural production.
Dissertations / Theses on the topic "Fungal Folate Pathway"
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Ngiam, Celina. "Characterisation of a foldase in the protein secretory pathway of Aspergillus niger." Thesis, University of East Anglia, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266738.
Full textBook chapters on the topic "Fungal Folate Pathway"
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Buchanan, Ruaridh, and Armine Sefton. "Mechanism of Action of Antimicrobial Agents." In Tutorial Topics in Infection for the Combined Infection Training Programme. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780198801740.003.0053.
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Antibacterial and antifungal agents aim to kill pathogens, or at the very least incapacitate them. To achieve this aim these agents must have a reasonable degree of toxicity at the cellular level. If this toxicity was equally manifest against all cell types then the drugs would be unusable in patients as the side effect profile would be unacceptably severe. Selective toxicity, whereby the agents are orders of magnitude more toxic to bacteria or fungi than human cells, allows for the safe and effective administration of these agents to patients. There are a number of different mechanisms by which an antimicrobial agent can yield selective toxicity: ● Target a cellular structure that exists only in bacteria/fungi—e.g. the cell wall; ● Target a cellular structure that has a significantly different structure in bacteria/ fungi— e.g. the ribosome; the fungal cell membrane; ● Target cellular enzymes that are significantly different in bacteria/fungi e.g. topoisomerase; ● Target a synthetic pathway that exists only in bacteria e.g. folate synthesis. Broadly, antibacterial drugs can be divided into the following categories: ● Agents that target the cell wall; ● Agents that target the cell membrane; ● Agents that inhibit protein synthesis; ● Agents that inhibit DNA replication/ transcription of RNA; ● Agents that target folate synthesis; ● Agents that directly damage intracellular structures. The cell wall is unique to bacteria, and therefore an ideal target. Disrupting the complex cross-linking process required to produce the cell wall leads to loss of bacterial cell integrity and therefore to cell death. The following classes of antibiotics target the cell wall: The first class to be discovered, and still in many cases the most effective, incorporates the four-membered beta-lactam ring—its homology to d-alanyl-d-alanine allows beta-lactam-containing compounds to bind to cell wall peptidoglycans and act as chain terminators. The beta-lactam ring is fused to a five-membered sulphur-containing ring. Variations in side chains account for the differing pharmacokinetics and spectra of action of the different compounds—for example, the addition of an amino group to benzylpenicillin produces ampicillin.