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Title:Structure and function of the terpene biosynthesis enzyme, IspH
Author(s):Rao, Guodong
Director of Research:Oldfield, Eric
Doctoral Committee Chair(s):Oldfield, Eric
Doctoral Committee Member(s):Gennis, Robert B.; Imlay, James A.; Jin, Hong
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Iron-sulfur cluster
Infectious diseases
Abstract:The protein IspH, (E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate reductase, is an essential enzyme in isoprenoid biosynthesis and an important drug/herbicide target. The main research in this work investigated the structures and functions of IspHs from various organisms. Using a sequence similarity network we found that some IspHs form "Rosetta-stone" fusion proteins with either the ribosomal protein S1 (RPS1), or a UbiA (4-hydroxybenzoate octaprenyltransferase)-like protein. These fusion proteins are all from obligately anaerobic bacteria. A catalytically active IspH-RPS1 was expressed and characterized. The existance of these fusion proteins is indicative of possible secondary roles of the enzyme IspH, perhaps being involved in O2 sensing and regulation. Using crystallographic and bioinformatics results we show that IspHs can be classified into four major classes, based on the arrangement of the aromatic residues near the 4Fe-4S cluster and the presence of N- and C-terminal extensions, and these structure features are related to the environments in which IspHs are found. These aromatic groups protect the 4Fe-4S clusters from oxidation and are also involved in electron transfer. The results revealed how nature has evolved different structure features for a sensitive protein in different environments. In addition, another terpene biosyntheis enzyme, MenA, and two other metalloenzymes that are drug targets, DHAD and LOX, were also investigated. Overall, this research is of interest since it revealed the structure and functions of the terpene biosynthesis enzyme IspH from various organisms, as well as other proteins that are possible drug targets.
Issue Date:2016-06-28
Rights Information:Copyright 2016 Guodong Rao
Date Available in IDEALS:2016-11-10
Date Deposited:2016-08

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