From genes to molecules: mining bacterial genomes for new enzyme reactions

点击翻译按钮获取中文摘要

Is it possible that a handful of soil or a pail of seawater could hold the solution to some of the pressing environmental and human health issues facing the world today? The advent of large scale DNA sequencing has revealed a molecular world that may indeed provide the answer to cleaning up pollutants or the path to the next wonder drug. Inspired by this new era of DNA driven discovery of new chemical reactions and molecules, we propose to explore enzymes that have the potential to improve environmental and human health. Specifically, we will study the remarkable carbon-phosphorus bond cleaving reaction of carbon-phosphorus lyase. We will also study the PhnY / PhnZ organophosphonate degradation system, recently identified through screening of marine DNA, which appears to cleave carbon-phosphorus bonds through a new reaction mechanism. Both enzyme systems have the potential to degrade environmental pollutants known as organophosphonates, a component of herbicides, insecticides, chemical warfare agents, and surfactants. We will also study enzymes that are involved in the biosynthesis of 'halogenated' natural products, a large family of bioactive molecules that have great potential to provide new anticancer and antibiotic drugs. Specifically we examine the unique reaction catalyzed by the 'halogenase' involved in the biosynthesis of one of the first wonder drugs of the 20th century, the antibiotic chloramphenicol. Using information gained from genome sequencing, we will also characterize the biosynthesis of, nucleocidin, a rare example of a fluorine substituted natural product. Identification of the enzyme that incorporates the fluorine atom, a 'fluorinase', could lead to a biocatalyst for the synthesis of fluorine containing nucleosides, which are of great interest as antiviral inhibitors. Overall our proposal contains 4 areas of study that will train 4 graduate students, as well as a yearly summer student, in a variety of skills, from molecular biology and microbiology to synthetic chemistry. These skills are in high demand in the increasingly multidisciplinary environment that exists in pharmaceutical and biotechnology companies.