title: Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase.
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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Chia-I
authors.initials: CI
authors.lastname: Liu
authors.forename: Wen-Yih
authors.initials: WY
authors.lastname: Jeng
authors.forename: Wei-Jung
authors.initials: WJ
authors.lastname: Chang
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Ko
authors.forename: Andrew H-J
authors.initials: AH
authors.lastname: Wang
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D013210:Staphylococcus / Q000201:enzymology*; D014233:Tricarboxylic Acids / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D013186:Farnesyl-Diphosphate Farnesyltransferase