2018 |
Rojas-Aedo, J F; Gil-Duran, C; Goity, A; Vaca, I; Levican, G; Larrondo, L F; Chavez, R The Developmental Regulator Pcz1 Affects the Production of Secondary Metabolites in the Filamentous Fungus Penicillium Roqueforti Artículo de revista Microbiological Research, 212 , pp. 67-74, 2018, ISSN: 0944-5013. Resumen | Enlaces | BibTeX | Etiquetas: biosynthesis, chrysogenum complex, cross-talk, discovery, expression, gene-cluster, laea, metabolism, mycophenolic-acid, pathway pcz1, penicillium protein, roqueforti, secondary subunit @article{RN382, title = {The Developmental Regulator Pcz1 Affects the Production of Secondary Metabolites in the Filamentous Fungus Penicillium Roqueforti}, author = { J.F. Rojas-Aedo and C. Gil-Duran and A. Goity and I. Vaca and G. Levican and L.F. Larrondo and R. Chavez}, url = {/brokenurl#<Go to ISI>://WOS:000438320100007}, doi = {10.1016/j.micres.2018.05.005}, issn = {0944-5013}, year = {2018}, date = {2018-01-01}, journal = {Microbiological Research}, volume = {212}, pages = {67-74}, abstract = {Penicillium roqueforti is used in the production of several kinds of ripened blue-veined cheeses. In addition, this fungus produces interesting secondary metabolites such as roquefortine C, andrastin A and mycophenolic acid. To date, there is scarce information concerning the regulation of the production of these secondary metabolites. Recently, the gene named pcz1 (Penicillium C6 zinc domain protein 1) was described in P. roqueforti, which encodes for a Zn(II)(2)Cys(6) protein that controls growth and developmental processes in this fungus. However, its effect on secondary metabolism is currently unknown. In this work, we have analyzed how the overexpression and down-regulation of pcz1 affect the production of roquefortine C, andrastin A and mycophenolic acid in P. roqueforti. The three metabolites were drastically reduced in the pcz1 down-regulated strains. However, when pcz1 was overexpressed, only mycophenolic acid was overproduced while, on the contrary, levels of roquefortine C and andrastin A were diminished. Importantly, these results match the expression pattern of keywords genes involved in the biosynthesis of these metabolites. Taken together, our results suggest that Pcz1 plays a keywords role in regulating secondary metabolism in the fungus Penicillium roqueforti.}, keywords = {biosynthesis, chrysogenum complex, cross-talk, discovery, expression, gene-cluster, laea, metabolism, mycophenolic-acid, pathway pcz1, penicillium protein, roqueforti, secondary subunit}, pubstate = {published}, tppubtype = {article} } Penicillium roqueforti is used in the production of several kinds of ripened blue-veined cheeses. In addition, this fungus produces interesting secondary metabolites such as roquefortine C, andrastin A and mycophenolic acid. To date, there is scarce information concerning the regulation of the production of these secondary metabolites. Recently, the gene named pcz1 (Penicillium C6 zinc domain protein 1) was described in P. roqueforti, which encodes for a Zn(II)(2)Cys(6) protein that controls growth and developmental processes in this fungus. However, its effect on secondary metabolism is currently unknown. In this work, we have analyzed how the overexpression and down-regulation of pcz1 affect the production of roquefortine C, andrastin A and mycophenolic acid in P. roqueforti. The three metabolites were drastically reduced in the pcz1 down-regulated strains. However, when pcz1 was overexpressed, only mycophenolic acid was overproduced while, on the contrary, levels of roquefortine C and andrastin A were diminished. Importantly, these results match the expression pattern of keywords genes involved in the biosynthesis of these metabolites. Taken together, our results suggest that Pcz1 plays a keywords role in regulating secondary metabolism in the fungus Penicillium roqueforti. |
2016 |
Polo, E; Trilleras, J; Ramos, J; Galdámez, A; Quiroga, J; Gutierrez, M Efficient Mw-Assisted Synthesis, Spectroscopic Characterization, X-Ray and Antioxidant Properties of Indazole Derivatives Artículo de revista Molecules, 21 (7), 2016, ISSN: 1420-3049. Resumen | Enlaces | BibTeX | Etiquetas: antioxidant chemistry, discovery, drug green heterocyclic impact, inhibitors, irradiation, microwave microwave, modern organic-synthesis, pyrazoles, synthesis, tetrahydroindazole @article{RN311, title = {Efficient Mw-Assisted Synthesis, Spectroscopic Characterization, X-Ray and Antioxidant Properties of Indazole Derivatives}, author = { E. Polo and J. Trilleras and J. Ramos and A. Gald\'{a}mez and J. Quiroga and M. Gutierrez}, url = {/brokenurl#<Go to ISI>://WOS:000381509700087}, doi = {UNSP 903, 10.3390/molecules21070903}, issn = {1420-3049}, year = {2016}, date = {2016-01-01}, journal = {Molecules}, volume = {21}, number = {7}, abstract = {A small series of tetrahydroindazoles was prepared, starting from 2-acetylcyclohexanone and different hydrazines using reflux and a focused microwave reactor. Microwave irradiation (MW) favored the formation of the desired products with improved yields and shortened reaction times. This is a simple and green method for the synthesis of substituted tetrahydroindazole derivatives. The in vitro antioxidant activity was evaluated using the DPPH and ABTS methods. In these assays, 2-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole (3f) showed moderate DPPH decoloring activity, while 3-methyl-4,5,6,7-tetrahydro-1H-indazole (3a), 3-methyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazole (3b) and 2-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole (3f) were the most active in the ABTS assay. All compounds were well characterized by IR, H-1-, C-13-NMR and GC-MS spectroscopy and physical data, while the structure of 4-(3-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzoic acid (3e) was also determined by single crystal X-ray analysis.}, keywords = {antioxidant chemistry, discovery, drug green heterocyclic impact, inhibitors, irradiation, microwave microwave, modern organic-synthesis, pyrazoles, synthesis, tetrahydroindazole}, pubstate = {published}, tppubtype = {article} } A small series of tetrahydroindazoles was prepared, starting from 2-acetylcyclohexanone and different hydrazines using reflux and a focused microwave reactor. Microwave irradiation (MW) favored the formation of the desired products with improved yields and shortened reaction times. This is a simple and green method for the synthesis of substituted tetrahydroindazole derivatives. The in vitro antioxidant activity was evaluated using the DPPH and ABTS methods. In these assays, 2-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole (3f) showed moderate DPPH decoloring activity, while 3-methyl-4,5,6,7-tetrahydro-1H-indazole (3a), 3-methyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazole (3b) and 2-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole (3f) were the most active in the ABTS assay. All compounds were well characterized by IR, H-1-, C-13-NMR and GC-MS spectroscopy and physical data, while the structure of 4-(3-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzoic acid (3e) was also determined by single crystal X-ray analysis. |
2015 |
Celis-Barros, C; Saavedra-Rivas, L; Salgado, J C; Cassels, B K; Zapata-Torres, G Molecular Dynamics Simulation of Halogen Bonding Mimics Experimental Data for Cathepsin L Inhibition Artículo de revista Journal of Computer-Aided Molecular Design, 29 (1), pp. 37-46, 2015, ISSN: 0920-654x. Resumen | Enlaces | BibTeX | Etiquetas: atherosclerosis, bonding, bromine cathepsin cathepsins, cysteine design, discovery, disease, drug force-field, halogen halogenated inhibitors, interactions, l, md optimization, protein-ligand sigma-hole, simulation @article{RN244, title = {Molecular Dynamics Simulation of Halogen Bonding Mimics Experimental Data for Cathepsin L Inhibition}, author = { C. Celis-Barros and L. Saavedra-Rivas and J.C. Salgado and B.K. Cassels and G. Zapata-Torres}, url = {/brokenurl#<Go to ISI>://WOS:000346913200004}, doi = {10.1007/s10822-014-9802-7}, issn = {0920-654x}, year = {2015}, date = {2015-01-01}, journal = {Journal of Computer-Aided Molecular Design}, volume = {29}, number = {1}, pages = {37-46}, abstract = {A MD simulation protocol was developed to model halogen bonding in protein-ligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. This protocol was then used to simulate the interactions of cathepsin L with a series of halogenated and non-halogenated inhibitors. Our results show that chloro, bromo and iodo derivatives have progressively narrower distributions of calculated geometries, which reflects the order of affinity I > Br > Cl, in agreement with the IC50 values. Graphs for the Cl, Br and I analogs show stable interactions between the halogen atom and the Gly61 carbonyl oxygen of the enzyme. The halogen-oxygen distance is close to or less than the sum of the van der Waals radii; the C-X center dot center dot center dot O angle is about 170A degrees; and the X center dot center dot center dot O=C angle approaches 120A degrees, as expected for halogen bond formation. In the case of the iodo-substituted analogs, these effects are enhanced by introduction of a fluorine atom on the inhibitors' halogen-bonding phenyl ring, indicating that the electron withdrawing group enlarges the sigma-hole, resulting in improved halogen bonding properties.}, keywords = {atherosclerosis, bonding, bromine cathepsin cathepsins, cysteine design, discovery, disease, drug force-field, halogen halogenated inhibitors, interactions, l, md optimization, protein-ligand sigma-hole, simulation}, pubstate = {published}, tppubtype = {article} } A MD simulation protocol was developed to model halogen bonding in protein-ligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. This protocol was then used to simulate the interactions of cathepsin L with a series of halogenated and non-halogenated inhibitors. Our results show that chloro, bromo and iodo derivatives have progressively narrower distributions of calculated geometries, which reflects the order of affinity I > Br > Cl, in agreement with the IC50 values. Graphs for the Cl, Br and I analogs show stable interactions between the halogen atom and the Gly61 carbonyl oxygen of the enzyme. The halogen-oxygen distance is close to or less than the sum of the van der Waals radii; the C-X center dot center dot center dot O angle is about 170A degrees; and the X center dot center dot center dot O=C angle approaches 120A degrees, as expected for halogen bond formation. In the case of the iodo-substituted analogs, these effects are enhanced by introduction of a fluorine atom on the inhibitors' halogen-bonding phenyl ring, indicating that the electron withdrawing group enlarges the sigma-hole, resulting in improved halogen bonding properties. |
Chavez, R; Fierro, F; Garcia-Rico, R O; Vaca, I Filamentous Fungi from Extreme Environments as a Promising Source of Novel Bioactive Secondary Metabolites Artículo de revista Frontiers in Microbiology, 6 , 2015, ISSN: 1664-302x. Resumen | Enlaces | BibTeX | Etiquetas: aspergillus-nidulans, biosynthetic clusters, discovery, drug environments, expression, extreme filamentous fungi, gene genome heterologous metabolites, metagenome, metagenomics, mining, natural natural-products, polyketide, products, resource, secondary sequence, strategy @article{RN241, title = {Filamentous Fungi from Extreme Environments as a Promising Source of Novel Bioactive Secondary Metabolites}, author = { R. Chavez and F. Fierro and R.O. Garcia-Rico and I. Vaca}, url = {/brokenurl#<Go to ISI>://WOS:000361157000001}, doi = {10.3389/fmicb.2015.00903}, issn = {1664-302x}, year = {2015}, date = {2015-01-01}, journal = {Frontiers in Microbiology}, volume = {6}, abstract = {Natural product search is undergoing resurgence upon the discovery of a huge previously unknown potential for secondary metabolite (SM) production hidden in microbial genomes. This is also the case for filamentous fungi, since their genomes contain a high number of "orphan" SM gene clusters. Recent estimates indicate that only 5% of existing fungal species have been described, thus the potential for the discovery of novel metabolites in fungi is huge. In this context, fungi thriving in harsh environments are of particular interest since they are outstanding producers of unusual chemical structures. At present, there are around 16 genomes from extreme environment-isolated fungi in databases. In a preliminary analysis of three of these genomes we found that several of the predicted SM gene clusters are probably involved in the biosynthesis of compounds not yet described. Genome mining strategies allow the exploitation of the information in genome sequences for the discovery of new natural compounds. The synergy between genome mining strategies and the expected abundance of SMs in fungi from extreme environments is a promising path to discover new natural compounds as a source of medically useful drugs.}, keywords = {aspergillus-nidulans, biosynthetic clusters, discovery, drug environments, expression, extreme filamentous fungi, gene genome heterologous metabolites, metagenome, metagenomics, mining, natural natural-products, polyketide, products, resource, secondary sequence, strategy}, pubstate = {published}, tppubtype = {article} } Natural product search is undergoing resurgence upon the discovery of a huge previously unknown potential for secondary metabolite (SM) production hidden in microbial genomes. This is also the case for filamentous fungi, since their genomes contain a high number of "orphan" SM gene clusters. Recent estimates indicate that only 5% of existing fungal species have been described, thus the potential for the discovery of novel metabolites in fungi is huge. In this context, fungi thriving in harsh environments are of particular interest since they are outstanding producers of unusual chemical structures. At present, there are around 16 genomes from extreme environment-isolated fungi in databases. In a preliminary analysis of three of these genomes we found that several of the predicted SM gene clusters are probably involved in the biosynthesis of compounds not yet described. Genome mining strategies allow the exploitation of the information in genome sequences for the discovery of new natural compounds. The synergy between genome mining strategies and the expected abundance of SMs in fungi from extreme environments is a promising path to discover new natural compounds as a source of medically useful drugs. |
2013 |
Vega, De La A P; Alarcon, D A; Gomez-Jeria, J S Journal of the Chilean Chemical Society, 58 (4), pp. 2148-2157, 2013, ISSN: 0717-9707. Resumen | Enlaces | BibTeX | Etiquetas: antigenic binding, c chemistry, core crystal-structure, dependent derivatives, discovery, hcv hepatitis ns5b nucleoside nucleotide, pharmacology, polymerase, protein, qsar, quantum replicons, rna-polymerase, site, structure-affinity, virus @article{RN169, title = {Quantum Chemical Study of the Relationships between Electronic Structure and Pharmacokinetic Profile, Inhibitory Strength toward Hepatitis C Virus Ns5b Polymerase and Hcv Replicons of Indole-Based Compounds}, author = { A.P. De La Vega and D.A. Alarcon and J.S. Gomez-Jeria}, url = {/brokenurl#<Go to ISI>://WOS:000331238800051}, doi = {10.4067/S0717-97072013000400055}, issn = {0717-9707}, year = {2013}, date = {2013-01-01}, journal = {Journal of the Chilean Chemical Society}, volume = {58}, number = {4}, pages = {2148-2157}, abstract = {This paper uses newly developed and extended quantum chemical methods in an attempt to advance the knowledge of the relationship between the variation of several local atomic descriptors of the electronic structure and the variation of the inhibitory capacity of a group of reversible and irreversible inhibitors of hepatitis C virus NS5B polymerase. Good structure-activity relationships were obtained for both kinds of compounds. Some processes are charge-, orbital- and/or steric-controlled. The action mechanisms seem to be different for reversible and irreversible inhibitors. Also, good QSAR equations were obtained for the activities of these compounds in a cellular replicon assay and for pharmacokinetic profiles. The local atomic hardness seems to give a good account of the interaction of the drugs with apolar sites of the partner (enzyme, receptor, etc.). This is the first time that a purely quantum-chemical index is able to deal directly with this kind of interaction.}, keywords = {antigenic binding, c chemistry, core crystal-structure, dependent derivatives, discovery, hcv hepatitis ns5b nucleoside nucleotide, pharmacology, polymerase, protein, qsar, quantum replicons, rna-polymerase, site, structure-affinity, virus}, pubstate = {published}, tppubtype = {article} } This paper uses newly developed and extended quantum chemical methods in an attempt to advance the knowledge of the relationship between the variation of several local atomic descriptors of the electronic structure and the variation of the inhibitory capacity of a group of reversible and irreversible inhibitors of hepatitis C virus NS5B polymerase. Good structure-activity relationships were obtained for both kinds of compounds. Some processes are charge-, orbital- and/or steric-controlled. The action mechanisms seem to be different for reversible and irreversible inhibitors. Also, good QSAR equations were obtained for the activities of these compounds in a cellular replicon assay and for pharmacokinetic profiles. The local atomic hardness seems to give a good account of the interaction of the drugs with apolar sites of the partner (enzyme, receptor, etc.). This is the first time that a purely quantum-chemical index is able to deal directly with this kind of interaction. |
2018 |
The Developmental Regulator Pcz1 Affects the Production of Secondary Metabolites in the Filamentous Fungus Penicillium Roqueforti Artículo de revista Microbiological Research, 212 , pp. 67-74, 2018, ISSN: 0944-5013. |
2016 |
Efficient Mw-Assisted Synthesis, Spectroscopic Characterization, X-Ray and Antioxidant Properties of Indazole Derivatives Artículo de revista Molecules, 21 (7), 2016, ISSN: 1420-3049. |
2015 |
Molecular Dynamics Simulation of Halogen Bonding Mimics Experimental Data for Cathepsin L Inhibition Artículo de revista Journal of Computer-Aided Molecular Design, 29 (1), pp. 37-46, 2015, ISSN: 0920-654x. |
Filamentous Fungi from Extreme Environments as a Promising Source of Novel Bioactive Secondary Metabolites Artículo de revista Frontiers in Microbiology, 6 , 2015, ISSN: 1664-302x. |
2013 |
Journal of the Chilean Chemical Society, 58 (4), pp. 2148-2157, 2013, ISSN: 0717-9707. |