Binding Modes of Zaragozic Acid A to Human Squalene Synthase and Staphylococcal Dehydrosqualene Synthase

• Published in: The Journal of biological chemistry 2012-05, Vol.287 (22), p.18750-18757
• Main Authors: Liu, Chia-I, Jeng, Wen-Yih, Chang, Wei-Jung, Ko, Tzu-Ping, Wang, Andrew H.-J.
• Format: Article
• Language: English
• Subjects: Bridged Bicyclo Compounds, Heterocyclic - metabolism; Drug Design; Farnesyl-Diphosphate Farnesyltransferase - chemistry; Farnesyl-Diphosphate Farnesyltransferase - metabolism; Fungal Metabolite; Humans; Hyperlipidemias; Models, Molecular; Protein Structure and Folding; Staphylococcus - enzymology; Staphylococcus aureus; Staphyloxanthin; Steroid; Structural Biology; Tricarboxylic Acids - metabolism; X-ray Crystallography
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.351254

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. Fungal metabolites, zaragozic acids, are potent inhibitors against squalene synthase and S. aureus dehydro-squalene synthase. Here we reported the zaragozic acid A binding mode for the head-to-head prenyltransferase drug targets. Zaragozic acid A presents an unexpected binding mode from the cyclopropyl-containing intermediate in both enzymes. Our structures provide a structural basis for development of potential drugs for hyperlipidemias and bacterial infection treatments.