Structure and Function of Fatty Acid Oxygenases
Our laboratory has a long-standing interest in enzymes of arachidonic acid oxygenation. This includes lipoxygenases, which incorporate one molecule of O2 into the carbon framework and cyclooxygenases, which incorporate two molecules of O2. The products of both pathways of oxygenation are substrates for metabolizing enzymes that generate a panoply of lipid mediators. Leukotrienes and prostaglandins are involved in multiple physiological and pathophysiological events, and inhibition of their action is the molecular basis for the pharmacological activities of several important drugs. Foremost among these are non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors. We have conducted extensive functional studies with lipoxygenases and cyclooxygenases based on available crystal structures employing exhaustive site-directed mutagenesis.
Recent attention in the laboratory has focused on our discovery that 2-arachidonylglycerol (2-AG) and arachidonylethanolamide (anandamide) are selective substrates for 12- and 15-lipoxygenase and cyclooxygenase-2. 2-AG and anandamide are the two known endogenous ligands for the cannabinoid receptors, so our discoveries provide a link between cannabinoid signaling and metabolism by lipoxygenases and cyclooxygenases. The discovery that 2-AG is a selective substrate for COX-2 is potentially important because it represents a clearcut biochemical difference between COX-1 and COX-2 and may help explain why COX-2 evolved as a separate gene. We are actively investigating the signal transduction pathways that lead to endocannabinoid release and the biological activities of their oxygenation products.
Recent Leading Articles:
K.R. Kozak and L.J. Marnett "Oxidative Metabolism of Endocannabinoids," Prostaglandins, Leuk.Essent.Fatty Acids, 66, 211-220 (2002).
[PubMed]
R.G. Kurumbail, J.R. Kiefer, and L.J. Marnett "Cyclooxygenase Enzymes: Catalysis and Inhibition," Curr.Opin.Struct.Biol, 11, 752-760 (2001).
J.S. Moody, K.R. Kozak, C. Ji, and L.J. Marnett "Selective Oxygenation of the Endocannabinoid, 2-Arachidonylglycerol, by Leukocyte-Type 12-Lipoxygenase." Biochemistry, 40, 861-866 (2001).
K.R. Kozak, J.J. Prusakiewicz, S.W. Rowlinson, C. Schneider, and L.J. Marnett "Amino Acid Determinants in Cyclooxygenase-2 Oxygenation of the Endocannabinoid 2-Arachidonylglycerol," J.Biol.Chem, 276, 30072-30077 (2001).
