Methyltransferase Specificity Toward Secondary Metabolite Production in Aspergillus niger

Secondary metabolites are bioactive compounds that demonstrate a broad chemical diversity and represent a source of pharmacologically and industrially relevant compounds. Bioactivities of secondary metabolites can be improved through chemical modification, or in vivo using an organism as a cell factory. As such, secondary metabolite modifications were examined in vivo using the Aspergillus niger secondary metabolite TAN-1612/BMS-192548 (TAN/BMS). The genes involved in the biosynthesis of TAN/BMS are organized in a biosynthetic gene cluster, and consist of a polyketide synthase backbone, tailoring enzymes including an O-methyltransferase, a transporter, and a fungal-specific transcription factor. In general, methyl group addition represents a strategy used to modify and optimize drugs, and methyltransferases represent an opportunity to explore methylation in vivo. Selective methylation was examined in a TAN/BMS overexpression and knockout strain through the homologous insertion of genes. To this end, an intraspecies methyltransferase gene library was designed and overexpressed in A. niger at the glucoamylase A (glaA) locus which is often exploited for enzyme overproduction. Screening methods were used to examine the expression profiles of the gene-edited strains. The overexpression of the native TAN/BMS methyltransferase gene in glaA was shown to partially restore TAN/BMS methylation. The methyltransferase mutants did not recapitulate nor modify the methylation pattern of TAN/BMS. Results indicated that the localization of genes may play an important role in selective methylation

The Human Gut Microbiota: Toward an Ecology of Disease

Composed of trillions of individual microbes, the human gut microbiota has adapted to the uniquely diverse environments found in the human intestine. Quickly responding to the variances in the ingested food, the microbiota interacts with the host via reciprocal biochemical signaling to coordinate the exchange of nutrients and proper immune function. Host and microbiota function as a unit which guards its balance against invasion by potential pathogens and which undergoes natural selection. Disturbance of the microbiota composition, or dysbiosis, is often associated with human disease, indicating that, while there seems to be no unique optimal composition of the gut microbiota, a balanced community is crucial for human health. Emerging knowledge of the ecology of the microbiota-host synergy will have an impact on how we implement antibiotic treatment in therapeutics and prophylaxis and how we will consider alternative strategies of global remodeling of the microbiota such as fecal transplants. Here we examine the microbiota-human host relationship from the perspective of the microbial community dynamics

Drug discovery and chemical probing in Drosophila

Flies are increasingly utilized in drug discovery and chemical probing in vivo, which are novel technologies complementary to genetic probing in fundamental biological studies. Excellent genetic conservation, small size, short generation time and over one hundred years of genetics make Drosophila an attractive model for rapid assay readout and use of analytical amounts of compound, enabling the experimental iterations needed in early drug development at a fraction of time and costs. Here, we describe an effective drug-testing pipeline using adult flies that can be easily implemented to study several disease models and different genotypes to discover novel molecular insight, probes, quality lead compounds, and develop novel prototype drugs.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Human Gut Microbiota: Toward an Ecology of Disease

Composed of trillions of individual microbes, the human gut microbiota has adapted to the uniquely diverse environments found in the human intestine. Quickly responding to the variances in the ingested food, the microbiota interacts with the host via reciprocal biochemical signaling to coordinate the exchange of nutrients and proper immune function. Host and microbiota function as a unit which guards its balance against invasion by potential pathogens and which undergoes natural selection. Disturbance of the microbiota composition, or dysbiosis, is often associated with human disease, indicating that, while there seems to be no unique optimal composition of the gut microbiota, a balanced community is crucial for human health. Emerging knowledge of the ecology of the microbiota-host synergy will have an impact on how we implement antibiotic treatment in therapeutics and prophylaxis and how we will consider alternative strategies of global remodeling of the microbiota such as fecal transplants. Here we examine the microbiota-human host relationship from the perspective of the microbial community dynamics