Koen van de Wetering, DVM, PhD
Assistant Professor
Contact
233 S. 10th Street
Bluemle Life Sciences Building, Room 419
Philadelphia, PA 19107
Koen van de Wetering, DVM, PhD
Assistant Professor
Education
Education
PhD, Biochemistry/Lung Surfactant, Utrecht University, Utrecht, NL - 2003
DVM, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NL - 1999
MS, Veterinary Research, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NL - 1996
BS, Veterinary Medicine, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NL - 1994
Postdoctoral
ABC Transporters/Metabolomics. Netherlands Cancer Institute, Amsterdam, NL - 2011
Most Recent Peer-Reviewed Publications
- A new perspective on intervertebral disc calcification—from bench to bedside
- ENPP1 enzyme replacement therapy improves ectopic calcification but does not rescue skeletal phenotype in a mouse model for craniometaphyseal dysplasia
- Loss of function mutation in Ank causes aberrant mineralization and acquisition of osteoblast-like-phenotype by the cells of the intervertebral disc
- A new enzymatic assay to quantify inorganic pyrophosphate in plasma
- The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals
Expertise & Research Interests
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.