Mechanistic studies of PHB biosynthesis

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DESCRIPTION (provided by applicant): Polyhydroxyalkanoates (PHAs) are a class of microbial polyesters produced by many bacteria as intracellular carbon and energy storage polymers. They display material properties ranging from thermoplastics to elastomers. An important characteristic of PHAs is their inherent biodegradability in various environments or biosystems. Thus, the desire to replace the conventional petrochemical-based plastics with biodegradable plastics in an environmentally friendly and economically competitive fashion has served an impetus for this project. The new engineered materials are expected find wide applications such as in heart valves and as scaffolds for tissue engineering. The long-term goal of this proposal is to identify and understand the machinery involved in PHA biosynthesis and its regulation. Specifically, in order to distinguish between the two elongation mechanisms proposed for the formation of polyhydroxybutyrates (PHBs), approaches involving chemical methods, in combination with the construction of mutant enzymes, to trap the polymerization intermediates will be employed. Crystal structures will greatly enhance the understanding of the elongation mechanism and help design mechanism-based inhibitors more rationally. However, to date, no crystals of PHB synthases have been obtained although some progress has been made. A series of compounds will be prepared and explored as covalent inhibitors of synthases in an effort to obtain their crystals along with mutagenetic methods. PHAs are of general interest as they possess properties that range from thermoplastics to elastomers and are biodegradable. Understanding the PHA biosynthesis is crucial to engineering new materials that are currently being examined for their applications such as in heart valves and as scaffolds for tissue engineering. The goal of this project is to identify and understand the machinary involved in PHA biosynthesis and its regulation.