van de Wetering, Koen
Koen van de Wetering, DVM, PhD
233 S. 10th Street
Philadelphia, PA 19107
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
ABC Transporters/Metabolomics. Netherlands Cancer Institute, Amsterdam, NL - 2011
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.
Most Recent Peer-Reviewed Publications
- Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells
- Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice
- Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum
- Insights into Pathomechanisms and Treatment Development in Heritable Ectopic Mineralization Disorders: Summary of the PXE International Biennial Research Symposium—2016
- Functional Rescue of ABCC6 Deficiency by 4-Phenylbutyrate Therapy Reduces Dystrophic Calcification in Abcc6–/–Mice
- Effects of Different Variants in the ENPP1 Gene on the Functional Properties of Ectonucleotide Pyrophosphatase/Phosphodiesterase Family Member 1
- MRP1 mediates folate transport and antifolate sensitivity in Plasmodium falciparum
- ATP-binding cassette subfamily C member 5 (ABCC5) functions as an efflux transporter of glutamate conjugates and analogs
- N-lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids
- ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation - Brief report
- ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release
- Morphine induces hyperalgesia without involvement of μ-opioid receptor or morphine-3-glucuronide
- ABCG2 functions as a general phytoestrogen sulfate transporter in vivo
- Lack of ABCG2 shortens latency of BRCA1-deficient mammary tumors and this is not affected by genistein or resveratrol
- Oral availability of cefadroxil depends on ABCC3 and ABCC4
- Transportomics: Screening for substrates of ABC transporters in body fluids using vesicular transport assays
- Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin
- Abcc2 (Mrp2), Abcc3 (Mrp3), and Abcg2 (Bcrp1) are the main determinants for rapid elimination of methotrexate and its toxic metabolite 7- hydroxymethotrexate in vivo
- Targeted Metabolomics Identifies Glucuronides of Dietary Phytoestrogens as a Major Class of MRP3 Substrates In Vivo
- Unimpaired immune functions in the absence of Mrp4 (Abcc4)