Sesquiterpene synthases are a family of unique cyclases found in a variety of microorganisms and plants. Each of the more than 200 known synthases catalyzes the formation of a distinct sesquiterpene from a single, common substrate, farnesyl diphosphate. The versatility and dynamic nature of these cyclases provide an excellent system for the study of fundamental mechanisms of enzyme catalysis, including molecular recognition and stereochemically-directed synthesis. To this end, potential mechanism- based inhibitors for the sesquiterpene cyclases, trichodiene synthase, have been designed to identify catalytically important amino acid residues involved in the formation of trichodiene, the parent hydrocarbon for the trichothecene family of antibiotics and mycotoxins. Among these compounds are hydrocarbon for the trichothecene family of antibiotics and mycotoxins. Among these compounds are the (E, E)-10-cyclopropylidene-, (E, E)-10-aziridinyl-and (E,E,Z)-12-methylidene-analogs of farnesyl diphosphate, and the reaction intermediate analog, (1R)-N, 4-Dimethyl-N- (3-aziridinylpropyl)-3-cyclohexenamine. These compounds incorporate an electrophilic moiety that, upon binding or activation by the cyclase, should effectively target a proposed active site base for alkylation. Subsequent activation by the cyclase, should effectively target a proposed active site base for alkylation. Subsequent amino acid sequencing of the modified enzyme to identify the alkylated residue would locate catalytically important amino acid residues of trichodiene synthase and provide insight into the strategies utilized by sesquiterpene synthases in the formation of diverse products from common substrates.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM019347-01
Application #
2522490
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1998-05-16
Project End
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Brown University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912