Probing the evolution of promiscuity and functiona.. (FuncEvoDupliGenes)
Probing the evolution of promiscuity and functional diversification among ancient gene duplicates
Date du début: 22 févr. 2013,
Date de fin: 21 févr. 2015
Gene duplication followed by sequence divergence is recognized as a key mechanism in evolution to generate functional innovations and enrich the complexity of genetic networks. Though gene duplication is frequently observed, the ensuing process leading to functional differentiation among gene duplicates remains obscure. Lack of this critical information has limited not just our fundamental understanding of protein evolution, but the success in engineering enzymes for industrial applications and our ability to predict evolution, for instance, mutations accessible to pathogens against antibiotic treatments. To fill this knowledge gap, I propose an integrative approach to bring mechanistic insights into the functional diversification among flavoprotein disulfide reductases (FDRs), namely glutathione reductases, lipoamide reductases, soluble transhydrogenases, and mercuric reductases. Diverged before the split between prokaryotes and eukaryotes, these ancient gene duplicates now participate in distinct branches of cell metabolism but maintain remarkable sequence and structure conservation. Furthermore, they exhibit the ability to turn over secondary substrates (i.e. promiscuity). I will address the evolutionary history, functional divergence, and mechanistic basis of promiscuity of FDRs, and explore their utility for biotechnology through the following steps: (1) phylogenetic reconstruction of ancestral FDRs to examine the functional shift from ancestral to extant FDRs, (3) directed evolution of one or more FDRs toward novel functions, (4) replaying gene duplication and functional divergence of FDRs in real-time by microbial evolution experiments. This project is aimed at answering core questions in molecular evolution and exploring the utility of promiscuous enzymes by bringing the applicant’s expertise in evolutionary analysis and microbial genetics to the host group that masters enzymology, chemical biology, and cutting-edge directed evolution techniques.
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