Development of flavonoid therapeutics: Transport mechanisms in the model eukaryote Dictyostelium discoideum

We are investigating the function of two members of the multidrug and toxin efflux (MATE) transporter family, which are ubiquitous throughout all living kingdoms. MATEs have a wide range of substrate targets, with transporters conferring the ability to facilitate the movement of single or many compounds (Omote et al., 2006). We have identified two genes encoding 'MATE' proteins in the model amoeba Dictyostelium discoideum, and are making knockout and reporter lines for physiological and imaging studies. Expression of the transporters at different life stages suggests the two have distinct and not redundant functions. The first transporter gene is transcribed in highest levels when cells signal to each other and aggregate. The second transporter gene is predominant earlier, when unicellular Dictyostelium cells prey on bacteria, and transcription also peaks later when cells have aggregated to form a motile, multicellular slug. We hope to address fundamental questions in the cell biology of this important model organism such as the role of the extracellular matrix and how it is formed; to study localisation of these proteins in the unicellular and multicellular life cycle; and also to contribute to work on the mechanisms of a flavonoid therapy for polycystic kidney disease which is under development by our collaborators (Waheed et al., 2014). In plants, it is hypothesised that so-called 'MATE' transporter proteins may be involved in flavonoid transport: currently there is sparse literature on the transport mechanisms that would allow/prevent this family of compounds reaching eukaryotic cellular targets.