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

Research output: Contribution to journalArticle

27 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)18750-18757
Number of pages8
JournalJournal of Biological Chemistry
Issue number22
Publication statusPublished - May 25 2012
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this