Vanderbilt Enzymatic and Nonenzymatic Lipid Oxidation in Human Health and Disease


VICB RESEARCH Enzymatic and Nonenzymatic Lipid Oxidation in Human Health and Disease
Polyunsaturated fatty acids are a key component of cell membranes. These lipids are subject to free radical peroxidation reactions, which occur nonenzymatically, leading to the formation of reactive electrophiles that can damage membranes, proteins, and DNA. These processes are increased under states of “oxidative stress” and contribute to the pathogenesis of a range of neurological, cardiovascular, and inflammatory diseases, obesity, and cancer. Ironically, nature has also harnessed these reactions through the function of lipoxygenase and cyclooxygenase enzymes that catalyze the controlled stereospecific peroxidation of polyunsaturated fatty acids to form a series of lipid signaling molecules. These lipid oxidation products regulate multiple immune, cardiovascular, neurological, and reproductive processes. The role of enzymatic and nonenzymatic lipid peroxidation in health and disease is a focus of research in a number of VICB member laboratories. Enzymatic lipid peroxidation is a major focus of Larry Marnett’s in depth studies of cyclooxygenase structure, function, and inhibition. The cyclooxygenase pathway is also the subject of Rich Breyer’s investigations on the signaling role of prostaglandins. These products of the cyclooxygenase pathway of arachidonic acid metabolism, exert their effects through specific G-protein coupled receptors. The Breyer lab seeks to understand every aspect of the molecular biology, biochemistry, and pharmacology of these receptors. In contrast, the lipoxygenase pathways are the primary focus for Alan Brash and Claus Schneider, who strive to characterize the enzymes involved and their chemical mechanisms. Nonenzymatic lipid peroxidation is the primary focus for Ned Porter, Dan Liebler, Jack Roberts, and Sean Davies, and an ongoing interest for Larry Marnett. The Porter lab strives to understand the chemical mechanisms of lipid peroxidation and how antioxidants can be used to prevent damaging oxidation reactions that contribute to disease. The Liebler laboratory is interested in the identity and chemistry of modification of proteins by lipid-derived electrophiles. The Roberts lab focuses on specific classes of lipid peroxidation products, the isoprostanes and neuroprostanes. They use isoprostane levels as a reliable marker for oxidative stress, and attempt to understand the biologic roles of both isoprostanes and neuroprostanes in various disease states. The Davies lab concentrates their efforts on the highly reactive isoketal products of lipid peroxidation, with a major interest in their role in obesity and aging. The Marnett lab works to characterize the protein- and DNA-damaging effects of the bis-electrophile products of nonenzymatic lipid peroxidation reactions. Image Source: Binding of Cholesterol to the Amyloid Precursor Protein as Helps to Explain the Relationship of Cholesterol Levels to Alzheimer's disease. Chuck Sanders Laboratory. A.J. Beel, et al, Biochemistry (2008) 47, 9428.
School of Medicine \| Vanderbilt University Medical Center \| Vanderbilt University \| Eskind Library \| Search \| Help \| Copyright © 2009, Educational Technology, Biomedical Research Education & Training For more information, please contact Webmaster.

Polyunsaturated fatty acids are a key component of cell membranes. These lipids are subject to free radical peroxidation reactions, which occur nonenzymatically, leading to the formation of reactive electrophiles that can damage membranes, proteins, and DNA. These processes are increased under states of “oxidative stress” and contribute to the pathogenesis of a range of neurological, cardiovascular, and inflammatory diseases, obesity, and cancer. Ironically, nature has also harnessed these reactions through the function of lipoxygenase and cyclooxygenase enzymes that catalyze the controlled stereospecific peroxidation of polyunsaturated fatty acids to form a series of lipid signaling molecules. These lipid oxidation products regulate multiple immune, cardiovascular, neurological, and reproductive processes. The role of enzymatic and nonenzymatic lipid peroxidation in health and disease is a focus of research in a number of VICB member laboratories.

Enzymatic lipid peroxidation is a major focus of Larry Marnett’s in depth studies of cyclooxygenase structure, function, and inhibition. The cyclooxygenase pathway is also the subject of Rich Breyer’s investigations on the signaling role of prostaglandins. These products of the cyclooxygenase pathway of arachidonic acid metabolism, exert their effects through specific G-protein coupled receptors. The Breyer lab seeks to understand every aspect of the molecular biology, biochemistry, and pharmacology of these receptors. In contrast, the lipoxygenase pathways are the primary focus for Alan Brash and Claus Schneider, who strive to characterize the enzymes involved and their chemical mechanisms.

Nonenzymatic lipid peroxidation is the primary focus for Ned Porter, Dan Liebler, Jack Roberts, and Sean Davies, and an ongoing interest for Larry Marnett. The Porter lab strives to understand the chemical mechanisms of lipid peroxidation and how antioxidants can be used to prevent damaging oxidation reactions that contribute to disease. The Liebler laboratory is interested in the identity and chemistry of modification of proteins by lipid-derived electrophiles. The Roberts lab focuses on specific classes of lipid peroxidation products, the isoprostanes and neuroprostanes. They use isoprostane levels as a reliable marker for oxidative stress, and attempt to understand the biologic roles of both isoprostanes and neuroprostanes in various disease states. The Davies lab concentrates their efforts on the highly reactive isoketal products of lipid peroxidation, with a major interest in their role in obesity and aging. The Marnett lab works to characterize the protein- and DNA-damaging effects of the bis-electrophile products of nonenzymatic lipid peroxidation reactions.

Image Source: Binding of Cholesterol to the Amyloid Precursor Protein as Helps to Explain the Relationship of Cholesterol Levels to Alzheimer's disease. Chuck Sanders Laboratory. A.J. Beel, et al, Biochemistry (2008) 47, 9428.