Head-to-head terpene synthases: Mechanism of action and inhibition

Lin, Fu-Yang

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https://hdl.handle.net/2142/24489 Copy

Description

Title

Head-to-head terpene synthases: Mechanism of action and inhibition

Author(s)

Lin, Fu-Yang

Issue Date

2011-05-25T14:27:33Z

Director of Research (if dissertation) or Advisor (if thesis)

Oldfield, Eric

Doctoral Committee Chair(s)

Oldfield, Eric

Committee Member(s)

• Gennis, Robert B.
• Nair, Satish K.
• Mitchell, Douglas A.

Department of Study

School of Molecular & Cell Bio

Discipline

Biophysics & Computnl Biology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• terpenes
• isoprenoids
• antibiotics
• virulence factor
• dehydrosqualene synthase
• Dehydrosqualene synthase (CrtM)
• squalene synthase (SQS)
• drug design
• high throughput screening

Abstract

“Head-to-head” terpene synthases catalyze the first committed steps in sterol and carotenoid biosynthesis: the condensation of two isoprenoid diphosphates to form cyclopropylcarbinyl diphosphates, followed by ring opening. In this work, I used x-ray crystallography, and mutagenesis to study the catalytic mechanism of Staphylococcus aureus dehydrosqualene synthase. Dehydrosqualene synthase (CrtM) is also the first committed enzyme in the biosynthesis of staphyloxanthin, a carotenoid pigment, and a major virulence factor in S. aureus. Inhibitors targeting CrtM and staphyloxanthin biosynthesis are therefore of interest as “anti-virulence” based therapy for treating S. aureus infection. I studied the structure-activity-relationship of phosphonosulfonate and phosphonoacetamide compounds in CrtM inhibition, and I also developed a series of non-phosphonate CrtM inhibitors using rational- and structure-based approaches.

Graduation Semester

2011-05

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http://hdl.handle.net/2142/24489

Copyright and License Information

Copyright 2011 Fu-Yang Lin

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