Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase

Chia I. Liu, Wen Yih Jeng, Wei Jung Chang, Tzu Ping Ko, Andrew H J Wang

研究成果: 雜誌貢獻文章同行評審

28 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)18750-18757
頁數8
期刊Journal of Biological Chemistry
287
發行號22
DOIs
出版狀態已發佈 - 五月 25 2012
對外發佈

ASJC Scopus subject areas

  • 生物化學
  • 細胞生物學
  • 分子生物學

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