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

24 Citations (Scopus)

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 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
Volume287
Issue number22
DOIs
Publication statusPublished - 2012 May 25

Fingerprint

Farnesyl-Diphosphate Farnesyltransferase
Oxidative stress
Sterols
Enzymes
Metabolites
Staphylococcus aureus
Oxidative Stress
Binding Sites
dehydrosqualene
squalestatin 1
Acids
Substrates

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Liu, Chia I. ; Jeng, Wen Yih ; Chang, Wei Jung ; Ko, Tzu Ping ; Wang, Andrew H.J. / Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 22. pp. 18750-18757.
@article{3d0f8d5263dc4acabe567fb81713e175,
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 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.",
author = "Liu, {Chia I.} and Jeng, {Wen Yih} and Chang, {Wei Jung} and Ko, {Tzu Ping} and Wang, {Andrew H.J.}",
year = "2012",
month = "5",
day = "25",
doi = "10.1074/jbc.M112.351254",
language = "English",
volume = "287",
pages = "18750--18757",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "22",

}

Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase. / Liu, Chia I.; Jeng, Wen Yih; Chang, Wei Jung; Ko, Tzu Ping; Wang, Andrew H.J.

In: Journal of Biological Chemistry, Vol. 287, No. 22, 25.05.2012, p. 18750-18757.

Research output: Contribution to journalArticle

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

VL - 287

SP - 18750

EP - 18757

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 22

ER -