The ABC gene family code for transporter proteins pumping a variety of compounds across the membranes of cells and tissues. Overexpression of ABC transporters is an important cause of multidrug resistance to chemotherapy agents and these genes are mutated in diverse human diseases. To understand the function of the ABCC6 gene causing pseudoxanthoma elasticum we have initiated a metabolomics study. Urine from male patients has been used to generate metabolite profiles. We have also initiated studies of serum and urine from Abcc6 -/- mice and from yeast cell deficient in an ABCC subfamily gene. These studies should aid us in identifying the substrate of this transporter. ABCG2 is an important drug resistance gene and we have screened for and identified new inhibitors. One of these is a new class of compounds known as botrylamides. The botrylamides are found in marine sponges and are simple enough chemically that derivatives can be synthesized and a structure/function relationship determined. ABCG2 is an important marker and resistance factor in cancer stem cells. Several of these compounds can be shown to inhibit substrate binding and/or ATPase activity of the protein. The complete complement of ABC genes was characterized in the sea urchin, a major model organism for development and cell biology. We find that the sea urchin has a dramatically expanded complement of drug transporter genes as well as orthologs of many human disease genes.
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