Fatty acid desaturases produce essential mono- and polyunsaturated lipids and thus help to maintain and control the function of cellular membranes. Diseases associated with changes in lipid composition include obesity, diabetes, hypertension, cardiovascular disease, immune disorders, skin diseases, and others. Desaturases also help to produce the mycolic acid coating that protects the human pathogen Mycobacterium tuberculosis from macrophage attack, dessication, water-soluble antibiotics, and other ameliorative agents. Despite the importance of unsaturated fatty acids in health and disease, many molecular details of desaturase reactions are poorly understood, including the reactivity of the required diiron centers, the contributions of protein interactions to catalysis, the nature of substrate intermediates formed during the reaction, and the mechanism(s) and consequences of reaction. Our long-term goal is to provide a more complete understanding of this essential catalytic process by study of representative soluble and integral membrane desaturases. A combination of biochemical, biophysical, kinetic, chemical and enzyme synthetic approaches will be used.
The Aim I studies will establish a program for study of the structure and function of desaturases required for mycolic acid biosynthesis.
The Aim II studies address how desaturases interact with their required protein and acyl chain partners to generate position-specific catalysis, which is a hallmark of these enzyme reactions.
The Aim III studies focus on the mechanism of electron transfer and redox control in desaturase reactions. Since all desaturases require reducing equivalents for catalysis, this work is of fundamental importance to understanding function.
The Aim I V studies will investigate the mechanism of covalent inactivation of stearoyl-CoA desaturase by cyclopropenyl fatty acids. The potential of using related molecules to inactivate other position-specific desaturases will be determined.
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