Koen van de Wetering, DVM, PhD

ABC transporters. Our group is interested in ATP binding Cassette (ABC) transporters of the C subfamily. ABC transporters are integral membrane proteins that translocate substrates at the expense of ATP hydrolysis. Our studies focus on the identification of the substrates transported by these efflux pumps in vivo by using highly innovative metabolomics-based approaches. Previous work from our group has resulted in the elucidation of the in vivo substrate spectrum of several ABC proteins, including the orphan transporter ABCC5, which we found to have a preference for compounds containing a glutamate moiety. Our metabolic screens even identified a whole new class of mammalian metabolites, the N-lactoyl amino acids.

ABC transporters, Dermatology and ectopic mineralization. Several ABC transporters are of clinical importance. An example is ABCC6. People lacking functionally active ABCC6 develop a disease known as pseudoxanthoma elasticum (PXE), a prototype, heritable, connective tissue disorder. PXE is characterized by pathological mineralization in skin, eyes and arteries. ABCC6 is predominantly found in the liver, and for a long time it was unclear why absence of an efflux pump in the liver results in precipitation of calcium phosphate in soft peripheral tissues.

Our untargeted metabolic screens resolved this issue, by showing that in hepatocytes ABCC6 mediates the release of ATP. Outside the hepatocytes, but still within the vasculature of the liver, released ATP is converted into AMP and pyrophosphate, a potent inhibitor of mineralization. PXE patients have low plasma concentrations in their blood and this explains why they develop a slowly progressive ectopic mineralization phenotype.

Current research interests. Finding an ABC transporter being involved in the release of ATP was unexpected. Other ABC transporters hydrolyze ATP intracellularly to pump specific compounds out of the cell. Substrates of ABC transporters include xenobiotics, hormones and metabolic waste products, no ABC transporter has been shown to pump ATP out of cells. Due to the huge gradient over the plasma membrane, an active transport mechanism would not even be needed to get ATP out of the cell. We now try to decipher the molecular details of ABCC6-mediated ATP release using a myriad of molecular biology-based and biochemical approaches.

We also are putting much effort in trying to use our breakthrough discovery that PXE is due to the absence of ABCC6-mediated ATP release and subsequent extracellular pyrophosphate formation to develop an efficient and specific therapy for this invalidating disease.