AUROTHIOMALATE

Enzyme inhibitor

This immunosuppressive (FW = 390.08 g/mol; CAS 12244-57-4; Symbol: AuTM), also known as sodium aurothiomalate, gold sodium thiomalate, Myocrisin?, and sodium 2- (auriosulfanyl) -3-carboxypropanoate, is an orally active nonsteroidal anti-inflammatory agent for treating rheumatism. See also Auranofin Even so, the demonstrated effectiveness of low-dose methotrexate (MTX) has led to a significant decline in using sodium aurothiomalate. Mode of Action: AuTM markedly inhibits DNA binding by the transcription factor AP-1, with less potent effects for AP-2, NF-1 and TFIID. In studies of the interactions of the progesterone receptor (or PR) with its DNA response element (or PRE), AuTM was found to regulate gene expression, again suggesting that inhibition of binding of a transcription factor to DNA is a likely mechanism. Electrophoretic mobility-shift assays showed that AP-1 DNA binding is inhibited by gold (I) thiolates and selenite, with IC values occurring of 5 μM and 1 50 μM, respectively. Thiomalate was without effect in the absence of gold (I), and other metal ions inhibited at higher concentrations, in a rank order correlating with their thiol binding affinities. Cysteine-to-serine mutants demonstrated that these effects of Au (I) and selenite require Cys272 and Cys154 in the DNA-binding domains of Jun and Fos, respectively. Gold (I) thiolates and selenite did not inhibit nonspecific protein binding to the AP-1 site and were at least an order of magnitude less potent as inhibitors of sequence-specific binding to the AP-2, TFIID, or NF1 sites compared with the AP-1 site. Note: Given the chemical reactivity of AuTM, is is likely that this agent may inhibit other thiol-dependent processes within cells.