Mechanistic investigations on polyprenyl transferases and multi-target antibiotic discovery
type: CreativeWork
description: Terpenoid biosynthesis plays essential structural and functional roles in almost all life forms. Prenyl transferases, enzymes involved in the isoprenoid metabolism related to prenyl chains, transfer allylic prenyl groups to acceptor molecules. Head-to-tail condensations, usually of allylic diphosphates (isoprene units), are catalyzed by head-to-tail prenyl transferases (commonly referred to prenyl diphosphate synthase), and produce regular terpenes which are by far the most common isoprenoid compounds. Head-to-middle prenyl transferases have been reported recently and they catalyze the formation of branched products which belong to irregular terpenes. Based on the stereochemical outcome of the linear products, head-to-tail prenyl transferases can be categorized to two major classes, trans- and cis- prenyl tranferases. Trans- prenyl transferases are critical players in bacterial respiratory systems while cis-prenyl transferases are involved in the biosynthesis of peptidoglycan, essential in bacterial cell wall synthesis. Thus, both classes of head-to-tail prenyl transferases are druggable targets in antibiotic development. In Chapter 2, I discuss the new series of lipophilic bisphosphonates that inhibit the growth of various bacteria and target multiple prenyl transferases. To determine and verify the enzyme targets of antibiotic leads, enzyme inhibition assays and bacterial rescue assays were performed. In Chapter 3, I discuss the antimicrobial agents phenylthiazoles which target bacterial UPPS, YubB (undecaprenyl diphosphate phosphatase (UPPP)) deducted from transposon mutagenesis. Putative inner membrane family proteins YubA and YubD are annotated as transporters and may also be targets because the compounds collapsed the proton motive force in membrane vesicles. Cis-prenyl transferase UPPS serves as a lipid carrier in cell wall peptidoglycan synthesis and catalyzes consecutive condensations of isopentenyl pyrophosphate (IPP) and farnesyl pyrophosphate (FPP) to pr…
abstract: Terpenoid biosynthesis plays essential structural and functional roles in almost all life forms. Prenyl transferases, enzymes involved in the isoprenoid metabolism related to prenyl chains, transfer allylic prenyl groups to acceptor molecules. Head-to-tail condensations, usually of allylic diphosphates (isoprene units), are catalyzed by head-to-tail prenyl transferases (commonly referred to prenyl diphosphate synthase), and produce regular terpenes which are by far the most common isoprenoid compounds. Head-to-middle prenyl transferases have been reported recently and they catalyze the formation of branched products which belong to irregular terpenes. Based on the stereochemical outcome of the linear products, head-to-tail prenyl transferases can be categorized to two major classes, trans- and cis- prenyl tranferases. Trans- prenyl transferases are critical players in bacterial respiratory systems while cis-prenyl transferases are involved in the biosynthesis of peptidoglycan, essential in bacterial cell wall synthesis. Thus, both classes of head-to-tail prenyl transferases are druggable targets in antibiotic development. In Chapter 2, I discuss the new series of lipophilic bisphosphonates that inhibit the growth of various bacteria and target multiple prenyl transferases. To determine and verify the enzyme targets of antibiotic leads, enzyme inhibition assays and bacterial rescue assays were performed. In Chapter 3, I discuss the antimicrobial agents phenylthiazoles which target bacterial UPPS, YubB (undecaprenyl diphosphate phosphatase (UPPP)) deducted from transposon mutagenesis. Putative inner membrane family proteins YubA and YubD are annotated as transporters and may also be targets because the compounds collapsed the proton motive force in membrane vesicles. Cis-prenyl transferase UPPS serves as a lipid carrier in cell wall peptidoglycan synthesis and catalyzes consecutive condensations of isopentenyl pyrophosphate (IPP) and farnesyl pyrophosphate (FPP) to pr…
author: Chen, Lu
language: en
keywords: biosynthesis, fragrance, monoterpenes, terpenes, isoprenoids, natural products, antibiotics, enzymes, protein structures, X-ray diffraction, structure elucidation, antibiotic resistance, C. elegans, VRE, multi-drug resistance, antimicrobial, prenyltransferase, product chain length, site-directed mutagenesis, enzymology, enzyme catalysis, multi-target antibiotics
date published: 2019-02-08T18:43:46Z
date modified: 2026-07-22T22:24:42Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/102925