Abstract
Multidrug and toxin extrusion (MATE) proteins are involved in the extrusion of endogenous compounds and xenobiotics across the plasma membrane. They are conserved from bacteria to mammals, with different numbers of genes within groups. Here, we present the first data on identification and functional characterization of Mate proteins in zebrafish (Danio rerio). Phylogenetic analysis revealed six Mates in teleost fish, annotated as Mate3–8, which form a distinct cluster separated from the tetrapod MATEs/Mates. Synteny analysis showed that zebrafish mate genes are orthologous to human MATEs. Gene expression analysis revealed that all the mate transcripts were constitutively and differentially expressed during embryonic development, followed by pronounced and tissue-specific expression in adults. Functional analyses were performed using transport activity assays with model substrates after heterologous overexpression of five zebrafish Mates in HEK293T cells. The results showed that zebrafish Mates interact with both physiological and xenobiotic substances but also substantially differ with respect to the interacting compounds and interaction strength in comparison to mammalian MATEs/Mates. Taken together, our data clearly indicate a potentially important role for zebrafish Mate transporters in zebrafish embryos and adults and provide a basis for detailed functional characterizations of single zebrafish Mate transporters.
Highlights
Absorption, distribution, metabolism and excretion (ADME) are processes that determine the trafficking of compounds through cells and tissues
We focused on elucidating their identity, gene expression, and transport properties to obtain the first comprehensive data set to help determine the possible roles of these transporters in zebrafish, an important model vertebrate species
We identified six mate genes in the zebrafish genome and found that fish Mate proteins clearly form a distinct cluster from tetrapod Multidrug and toxin extrusion (MATE)/Mates (Fig. 1)
Summary
Absorption, distribution, metabolism and excretion (ADME) are processes that determine the trafficking of compounds through cells and tissues. ABC transporters form a large superfamily of ATP-dependent proteins that mediate the active transport of a vast array of structurally and chemically diverse physiological and xenobiotic substrates across biological membranes. Their role in multidrug (MDR)- and multixenobiotic-resistance (MXR) phenotypes has been extensively studied in mammals and fish[2]. Unlike human MATEs, mouse and rat Mate[2] are found only in the testes[10] Based on their transport function, MATE/Mate proteins are polyspecific transporters that mediate the efflux of cationic compounds, e.g., model cations, such as tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP+), or weak bases that are positively charged at physiological pH (e.g., cimetidine and metformin)[17]. An initial functional characterization of selected proteins was performed using transport activity assays with model substrates after heterologous overexpression of zebrafish Mates in HEK293T cells
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