NDST3 Inhibitors

Chemical inhibitors of N-deacetylase/N-sulfotransferase (NDST3) disrupt the protein's role in modulating heparan sulfate chains through various biochemical mechanisms. Suramin, for instance, blocks the action of heparanase, which ordinarily cleaves heparan sulfate. The inhibition of heparanase may lead to an accumulation of heparan sulfate chains, thereby hindering the ability of NDST3 to further process these molecules. Methylthiouracil interferes with the synthesis of thyroid hormones, which indirectly can influence sulfotransferase activities, including those performed by NDST3. In a similar vein, Sodium chlorate acts as an inhibitor of ATP sulfurylase, thereby reducing the availability of the essential sulfate donor PAPS, which is critical for NDST3's sulfation activity. Brefeldin A and Tunicamycin disrupt NDST3 through mechanisms affecting its localization and post-translational modification. Brefeldin A disrupts the Golgi apparatus, where NDST3 is localized and operates, impeding the sulfation of heparan sulfate. Tunicamycin hampers N-linked glycosylation, a process necessary for the proper functioning of NDST3. Quercetin directly inhibits the sulfotransferase function of NDST3, thereby reducing the sulfation of heparan sulfate. Sodium arsenate compromises energy metabolism, which is essential for the energy-dependent sulfation reactions that NDST3 catalyzes. Lithium chloride targets glycogen synthase kinase 3 (GSK3), a kinase that may affect NDST3 function. The inhibitors Fumonisin B1 and Clioquinol affect NDST3 by disrupting cellular membrane integrity and chelating metal ions, respectively. Fumonisin B1 impedes the synthesis of sphingolipids, components of the cellular membrane that are crucial for cell signaling and membrane-associated functions of proteins like NDST3. Clioquinol chelates zinc, a cofactor that maintains the structural integrity of many enzymes, including NDST3. Lastly, Trientine sequesters copper, which is vital for various enzymes, and its chelating action can alter NDST3's efficacy in modifying heparan sulfate.