Grant: Discovery Grants Program - Individual

Our laboratory is engaged in the study of an important group of biological catalysts known as fatty acid modifying enzymes. These proteins are widely distributed in all life-forms and modifiy fatty acid components via highly selective chemistry. The primary focus of our research program is to understand the molecular mechanisms which control the functional outcome as well as the exquisite regio- and stereoselectivity of these enzymic processes. We have developed a series of probes for this purpose and these tools are now being used by several groups in Canada, USA and Europe to study related systems. We plan to continue our fundamental studies with special emphasis on those systems for which 3-D structural information is being obtained. In this manner, emerging trends in reactivity can be correlated with accurate active site models. Our research has potential applications in four important areas: 1) Desaturase-derived plant oils have an annual global value of approximately 80 billion dollars and represent a significant portion of the Canadian economy. The ability to add value to these materials by altering the nature of their functional groups will enable the production of customer-defined oils destined for the chemical, pharmaceutical, cosmetic or food industries. In principle, this can be achieved through protein engineering experiments and the results of our mechanistic investigations should serve as an intellectual basis for future work in this area. 2) A number of lipidic plant constituents appear to act as species-specific defence agents. A deeper understanding of this highly sophisticated molecular warfare might lead to new strategies for integrated pest management. 3) A mammalian desaturase known as SCD-1 have been implicated in the management of disorders related to fat metabolism such as diabetes, atherosclerosis and cancer. Specific mechanism-based inhibitors of this enzyme are now being sought in an attempt to modulate SCD-1 activity and to more fully understand its cellular role 4) Cyclopropane synthases contribute to the virulency of Mycobacteria - the causative agents of tuberculosis and are now considered as therapeutic targets. Detailed mechanistic studies of these enzymes are clearly warranted.