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

“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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biophysics & Computnl Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2011

Author dc:creator

• Lin, Fu-Yang

Contributors dc:contributor

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

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

Statement dc:rights

• Copyright 2011 Fu-Yang Lin

Language dc:language

en

Handle dc:identifier

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

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/24489