Interconnected Set of Enzymes Provide Lysine Biosynthetic Intermediates and Ornithine Derivatives as Key Precursors for the Biosynthesis of Bioactive Secondary Metabolites.

Bacteria, filamentous fungi, and plants synthesize thousands of secondary metabolites with important biological and pharmacological activities. The biosynthesis of these metabolites is performed by networks of complex enzymes such as non-ribosomal peptide synthetases, polyketide synthases, and terpenoid biosynthetic enzymes. The efficient production of these metabolites is dependent upon the supply of precursors that arise from primary metabolism.

Penicillin-Binding Proteins, β-Lactamases, and β-Lactamase Inhibitors in β-Lactam-Producing Actinobacteria: Self-Resistance Mechanisms.

The human society faces a serious problem due to the widespread resistance to antibiotics in clinical practice. Most antibiotic biosynthesis gene clusters in actinobacteria contain genes for intrinsic self-resistance to the produced antibiotics, and it has been proposed that the antibiotic resistance genes in pathogenic bacteria originated in antibiotic-producing microorganisms. The model actinobacteria produces the β-lactam antibiotic cephamycin C, a class A β-lactamase, and the β lactamases inhibitor clavulanic acid, all of which are encoded in a gene supercluster; in addition, it synthesizes the β-lactamase inhibitory protein BLIP.

Streptomyces clavuligerus: The Omics Era.

The Streptomyces clavuligerus genome consists in a linear chromosome of about 6.7 Mb and four plasmids (pSCL1 to pSCL4), the latter one of 1.8 Mb.

Modulation of Gene Expression in Actinobacteria by Translational Modification of Transcriptional Factors and Secondary Metabolite Biosynthetic Enzymes.

Different types of post-translational modifications are present in bacteria that play essential roles in bacterial metabolism modulation. Nevertheless, limited information is available on these types of modifications in actinobacteria, particularly on their effects on secondary metabolite biosynthesis. Recently, phosphorylation, acetylation, or phosphopantetheneylation of transcriptional factors and key enzymes involved in secondary metabolite biosynthesis have been reported.

Molecular Mechanisms of Phosphate Sensing, Transport and Signalling in Streptomyces and Related Actinobacteria.

Phosphorous, in the form of phosphate, is a key element in the nutrition of all living beings. In nature, it is present in the form of phosphate salts, organophosphates, and phosphonates. Bacteria transport inorganic phosphate by the high affinity phosphate transport system PstSCAB, and the low affinity PitH transporters.

Purification and Chemical Characterization of a Potent Acaricide and a Closely Related Inactive Metabolite Produced by C47.

Mites are arthropods and some of them infest dry meat cured products and produce allergic reactions. Some mites, such as , or feed on filamentous fungi that grow during the meat curing process. Removal of mite infestation of meat products is extremely difficult and there are no adequate miticidal compounds.

The Balance Metabolism Safety Net: Integration of Stress Signals by Interacting Transcriptional Factors in and Related Actinobacteria.

Soil dwelling species are faced with large variations in carbon or nitrogen sources, phosphate, oxygen, iron, sulfur, and other nutrients. These drastic changes in key nutrients result in an unbalanced metabolism that have undesirable consequences for growth, cell differentiation, reproduction, and secondary metabolites biosynthesis. In the last decades evidence has accumulated indicating that mechanisms to correct metabolic unbalances in species take place at the transcriptional level, mediated by different transcriptional factors.

Regulation of Geldanamycin Biosynthesis by Cluster-Situated Transcription Factors and the Master Regulator PhoP.

Geldanamycin and the closely related herbimycins A, B, and C are benzoquinone-type ansamycins with antitumoral activity. They are produced by var. , and among other strains.

Sensing and transduction of nutritional and chemical signals in filamentous fungi: Impact on cell development and secondary metabolites biosynthesis.

Filamentous fungi respond to hundreds of nutritional, chemical and environmental signals that affect expression of primary metabolism and biosynthesis of secondary metabolites. These signals are sensed at the membrane level by G protein coupled receptors (GPCRs). GPCRs contain usually seven transmembrane domains, an external amino terminal fragment that interacts with the ligand, and an internal carboxy terminal end interacting with the intracellular G protein.

Activation of Secondary Metabolite Gene Clusters in by the PimM Regulator of .

Expression of non-native transcriptional activators may be a powerful general method to activate secondary metabolites biosynthetic pathways. PAS-LuxR regulators, whose archetype is PimM, activate the biosynthesis of polyene macrolide antifungals and other antibiotics, and have been shown to be functionally preserved across multiple strains. In this work we show that constitutive expression of in ATCC 27064 significantly affected its transcriptome and modifies secondary metabolism.

Harnessing microbiota interactions to produce bioactive metabolites: communication signals and receptor proteins.

Numerous microbial communities live in soil, aquatic habitats, plants, and animal bodies. Microbial genome sequences have revealed that thousands of biosynthetic gene clusters (BGCs) are present in different bacteria and filamentous fungi. Many of these BGCs are not expressed in pure cultures in the laboratory.

Transcriptional Studies on a Deletion Mutant: -Acetylglycyl-Clavaminic Acid Is an Intermediate of Clavulanic Acid Biosynthesis.

The gene encodes an oligopeptide-binding protein similar to the periplasmic substrate-binding proteins of the ABC transport systems. However, is an orphan gene, not included in an ABC operon. This gene is located in the clavulanic acid (CA) gene cluster of and is essential for CA production.

ArgR of Is a Pleiotropic Transcriptional Regulator: Effect on the Transcriptome, Antibiotic Production, and Differentiation in Liquid Cultures.

ArgR is a well-characterized transcriptional repressor controlling the expression of arginine and pyrimidine biosynthetic genes in bacteria. In this work, the biological role of ArgR was analyzed by comparing the transcriptomes of Δ and its parental strain, M145, at five different times over a 66-h period. The effect of ArgR was more widespread than that of the orthologous protein of , affecting the expression of 1544 genes along the microarray time series.

Clavine Alkaloids Gene Clusters of and Related Fungi: Evolutionary Combination of Prenyltransferases, Monooxygenases and Dioxygenases.

The clavine alkaloids produced by the fungi of the Aspergillaceae and Arthrodermatacea families differ from the ergot alkaloids produced by and . The clavine alkaloids lack the extensive peptide chain modifications that occur in lysergic acid derived ergot alkaloids. Both clavine and ergot alkaloids arise from the condensation of tryptophan and dimethylallylpyrophosphate by the action of the dimethylallyltryptophan synthase.

Streptomyces tsukubaensis as a new model for carbon repression: transcriptomic response to tacrolimus repressing carbon sources.

In this work, we identified glucose and glycerol as tacrolimus repressing carbon sources in the important species Streptomyces tsukubaensis. A genome-wide analysis of the transcriptomic response to glucose and glycerol additions was performed using microarray technology. The transcriptional time series obtained allowed us to compare the transcriptomic profiling of S.

Silencing of a second dimethylallyltryptophan synthase of Penicillium roqueforti reveals a novel clavine alkaloid gene cluster.

Penicillium roqueforti produces several prenylated indole alkaloids, including roquefortine C and clavine alkaloids. The first step in the biosynthesis of roquefortine C is the prenylation of tryptophan-derived dipeptides by a dimethylallyltryptophan synthase, specific for roquefortine biosynthesis (roquefortine prenyltransferase). A second dimethylallyltryptophan synthase, DmaW2, different from the roquefortine prenyltransferase, has been studied in this article.

The master regulator PhoP coordinates phosphate and nitrogen metabolism, respiration, cell differentiation and antibiotic biosynthesis: comparison in Streptomyces coelicolor and Streptomyces avermitilis.

Phosphate limitation is important for production of antibiotics and other secondary metabolites in Streptomyces. Phosphate control is mediated by the two-component system PhoR-PhoP. Following phosphate depletion, PhoP stimulates expression of genes involved in scavenging, transport and mobilization of phosphate, and represses the utilization of nitrogen sources.

Evolutionary formation of gene clusters by reorganization: the meleagrin/roquefortine paradigm in different fungi.

The biosynthesis of secondary metabolites in fungi is catalyzed by enzymes encoded by genes linked in clusters that are frequently co-regulated at the transcriptional level. Formation of gene clusters may take place by de novo assembly of genes recruited from other cellular functions, but also novel gene clusters are formed by reorganization of progenitor clusters and are distributed by horizontal gene transfer. This article reviews (i) the published information on the roquefortine/meleagrin/neoxaline gene clusters of Penicillium chrysogenum (Penicillium rubens) and the short roquefortine cluster of Penicillium roqueforti, and (ii) the correlation of the genes present in those clusters with the enzymes and metabolites derived from these pathways.

Molecular genetics of naringenin biosynthesis, a typical plant secondary metabolite produced by Streptomyces clavuligerus.

Background: Some types of flavonoid intermediates seemed to be restricted to plants. Naringenin is a typical plant metabolite, that has never been reported to be produced in prokariotes. Naringenin is formed by the action of a chalcone synthase using as starter 4-coumaroyl-CoA, which in dicotyledonous plants derives from phenylalanine by the action of a phenylalanine ammonia lyase.

The Pathway-Specific Regulator ClaR of Streptomyces clavuligerus Has a Global Effect on the Expression of Genes for Secondary Metabolism and Differentiation.

Streptomyces clavuligerus claR::aph is a claR-defective mutant, but in addition to its claR defect it also carries fewer copies of the resident linear plasmids pSCL2 and pSCL4 (on the order of 4 × 10(5)-fold lower than the wild-type strain), as shown by qPCR. To determine the function of ClaR without potential interference due to plasmid copy number, a new strain, S. clavuligerus ΔclaR::aac, with claR deleted and carrying the wild-type level of plasmids, was constructed.