Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6).

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Ilias A, Urban Z, Seidl TL, Le Saux O, Sinko E, Boyd CD, Sarkadi B, Varadi A

Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6).

J Biol Chem. 2002 May 10;277(19):16860-7. Epub 2002 Mar 5.

PubMed ID

11880368 [ View in PubMed

]

Abstract

Mutations in the ABCC6 (MRP6) gene cause pseudoxanthoma elasticum (PXE), a rare heritable disorder resulting in the calcification of elastic fibers. In the present study a cDNA encoding a full-length normal variant of ABCC6 was amplified from a human kidney cDNA library, and the protein was expressed in Sf9 insect cells. In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. Organic anions (probenecid, benzbromarone, indomethacin), known to interfere with glutathione conjugate transport of human ABCC1 and ABCC2, inhibited the ABCC6-mediated NEM-GS transport in a specific manner, indicating that ABCC6 has a unique substrate specificity. We have also expressed three missense mutant forms of ABCC6, which have recently been shown to cause PXE. MgATP binding was normal in these proteins; ATP-dependent NEM-GS or leukotriene C(4) transport, however, was abolished. Our data indicate that human ABCC6 is a primary active transporter for organic anions. In the three ABCC6 mutant forms examined, the loss of transport activity suggests that these mutations result in a PXE phenotype through a direct influence on the transport activity of this ABC transporter.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
ATP	Multidrug resistance-associated protein 6	Protein	Humans	Unknown	Not Available	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Indomethacin	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor	Details
Indomethacin	Multidrug resistance-associated protein 6	Protein	Humans	Unknown	Inhibitor	Details
Probenecid	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Probenecid	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor	Details
Probenecid	Multidrug resistance-associated protein 6	Protein	Humans	Unknown	Inhibitor	Details

Polypeptides

Name	UniProt ID
Multidrug resistance-associated protein 6	O95255	Details