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

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

Lin, Fu-Yang

关键词: terpenes;    isoprenoids;    antibiotics;    virulence factor;    dehydrosqualene synthase;    Dehydrosqualene synthase (CrtM);    squalene synthase (SQS);    drug design;    high throughput screening;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/24489/Lin_FuYang.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

“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.