By establishing a library of individual yeast genes, each cleverly tagged with its own molecular barcode, an international team of molecular geneticists has designed a valuable resource for pharmaceutical research with advantages over previous approaches.
The research team, including Minoru Yoshida at the RIKEN Advanced Science Institute in Wako, and Charles Boone at the University of Toronto, Canada, developed the library in which each yeast gene is copied and attached to two unique single stranded DNA molecules that act as barcodes. This enables researchers to efficiently identify each gene.
The yeast-based chemical-genomics approach, presented recently in Nature Biotechnology by Yoshida and colleagues (1), is useful because many medicinally important drugs target fundamental biological processes that are conserved between yeast cells and higher organisms.
Using the team’s approach, all the gene-carrying units, or plasmids, in the yeast are carefully constructed individually, as opposed to conventional genomic libraries that are created from random fragments of DNA. Each plasmid carries a single yeast gene as well as two 20-nucleotide barcodes that identify it. The library comprises plasmids for almost 5,000 genes and covers approximately 90% of the yeast genome.
Other approaches to examine the genetic influence of potential drugs have limitations such as needing high volumes of test compound, which can be of limited availability, or being labor intensive.
Most significantly, the newly created gene catalogue will enable researchers to identify at the genetic level the precise modes of action of specific compounds that are being screened as potential pharmaceuticals. The library can be used to efficiently identify mutant genes that confer resistance to a test drug by comparing cells that show resistance and susceptibility to the compound. Determination of the mutant genes leads to the identification of the functional impact of a potential drug.
In a demonstration of the usefulness of the library, Yoshida and colleagues identified the gene responsible for conferring resistance to a novel class of compounds with pharmaceutical potential. Identifying this gene enabled the team to characterize the mechanism of action of these molecules and to determine that they are antifungal compounds, a property not detected by other techniques.
An essential but challenging step in the development of small molecules into therapeutic drugs is identification of their cellular target. “Using this library, our group intends systematically to study chemical–genetic interactions in which an altered gene dosage or gene mutation leads to a change in cellular response to a bioactive compound,” says Yoshida.
Ho, C.H., Magtanong, L., Barker, S.L., Gresham, D., Nishimura, S., Natarajan, P., Koh, J.L.Y., Porter, J., Gray, C.A., Andersen, R.J. et al. A molecular barcoded yeast ORF library enables mode-of-action analysis of bioactive compounds. Nature Biotechnology 27, 369–377 (2009).
The corresponding author for this highlight is based at the RIKEN Chemical Biology Department, Chemical Genomics Research Group
For a chimpanzee, one good turn deserves another
27.06.2017 | Max-Planck-Institut für Mathematik in den Naturwissenschaften (MPIMIS)
New method to rapidly map the 'social networks' of proteins
27.06.2017 | Salk Institute
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
27.06.2017 | Power and Electrical Engineering
27.06.2017 | Information Technology
27.06.2017 | Physics and Astronomy