Nucleobases and nucleosides play a key role in nucleic acid and nucleotide metabolism in all cells, act as signalling molecules, neuromodulators and serve as nitrogen source in plants and many micro-organisms. They are synthesised de novo or, when de novo synthesis pathways are lacking, salvaged from the environment (purine auxotroph parasites; specialised mammalian cell types). Transport of nucleobases and nucleosides across biological membranes is mediated by specific transport proteins. Nucleobase- and nucleoside transporters have been identified and characterised in a variety of pro- and eukaryotes. However, due to the limited amount of molecular data, it remained unknown how the secondary structure determines the substrate-specificity of the transporters.
Many antiviral and anticancer nucleoside drugs are substrates of nucleoside and some of the nucleobase transporters, such as 5-fluoro uracil, 5-fluoro uridine and their derivatives. Since the transport of nucleoside drugs is critical to their therapeutic effectiveness, understanding the molecular mechanism of the transport process could enable the design of more effective nucleoside drugs and those with better absorption profile. Currently, the rational design of these drugs is hindered by the absence of high-resolution structural data on the transporters. Revealing the structure-activity relationships of transporters could facilitate the discovery of novel drugs with affinity specific for particular transporters.
This project intends to investigate the uracil and uridine substrate specific nucleobase and nucleoside transporters of the model organism, A. nidulans, and subject them to mutational analysis using a complex molecular biological strategy to generate and characterise various functional mutant derivatives of these proteins, which will finally lead to a better understanding of the structure and specificity (and the relationship between these two) of the transporters molecules.
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