Zaragozic acids (ZAs) belong to a family of fungal metabolites with nanomolar inhibitory activity toward squalene synthase (SQS). The enzyme catalyzes the committed step of sterol synthesis and has attracted attention as a potential target for antilipogenic and antiinfective therapies. Here, we have determined the structure of ZA-A complexed with human SQS. ZA-A binding induces a local conformational change in the substrate binding site, and its C-6 acyl group also extends over to the cofactor binding cavity. In addition, ZA-A effectively inhibits a homologous bacterial enzyme, dehydrosqualene synthase (CrtM), which synthesizes the precursor of staphyloxanthin in Staphylococcus aureus to cope with oxidative stress. Size reduction at Tyr248 in CrtM further increases the ZA-A binding affinity, and it reveals a similar overall inhibitor binding mode to that of human SQS/ZA-A except for the C-6 acyl group. These structures pave the way for further improving selectivity and development of a new generation of anticholesterolemic and antimicrobial inhibitors.
ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Liu, C. I., Jeng, W. Y., Chang, W. J., Ko, T. P., & Wang, A. H. J. (2012). Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase. Journal of Biological Chemistry, 287(22), 18750-18757. https://doi.org/10.1074/jbc.M112.351254