Abstract
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 Tyr(248) 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.
Highlights
Fungal metabolites, zaragozic acids, are potent inhibitors against squalene synthase and S. aureus dehydrosqualene synthase
We obtained the structures of the ligand-free human squalene synthase (SQS) and its complex with Zaragozic acids (ZAs)-A in four different crystal forms, and the refinement statistics are shown in supplemental Table S1
As ZAs exhibit fascinating biological activity for SQS, much work has focused on total synthesis by Merck, Glaxo, and other groups in an attempt to identify the key structural features of SQS-inhibitory activity [9, 20, 21, 33,34,35,36,37]
Summary
Zaragozic acids, are potent inhibitors against squalene synthase and S. aureus dehydrosqualene synthase. 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. In this report we provide x-ray crystal structures of the ligand-free human SQS with two flexible regions for ligand binding, ZA-A in complex with human SQS and S. aureus CrtM, and we analyze the binding properties in vitro These structures provide the detailed, high resolution view of the binding interactions and conformational changes of ZA-A with these two important enzymes. Possible therapeutic applications include cholesterol-lowering agents, antiprotozoan and antimicrobial therapy
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