TY - JOUR
T1 - Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase
AU - Liu, Chia I.
AU - Jeng, Wen Yih
AU - Chang, Wei Jung
AU - Ko, Tzu Ping
AU - Wang, Andrew H.J.
PY - 2012/5/25
Y1 - 2012/5/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861560299&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861560299&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.351254
DO - 10.1074/jbc.M112.351254
M3 - Article
C2 - 22474324
AN - SCOPUS:84861560299
SN - 0021-9258
VL - 287
SP - 18750
EP - 18757
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 22
ER -