1 Lipid Mediators: Synthesis, Lipid Mediators: Synthesis, Metabolism, and Function Metabolism, and Function Biochemistry 201 Oct 23, 2007 Electa Park Overview Overview • Biological function of lipid mediators • Arachidonic acid (AA) synthesis • AA metabolites and related enzymes – Prostaglandins, thromboxanes, leukotrienes • EETS, Lipoxins, Isoprostanes • Inhibiton of AA metabolizing enzymes • Receptors and Metabolism
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Lipid Mediators: Synthesis, Metabolism, and Function · –Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) •Salicylates •Arylpropionic acid derivatives – Ibuprofen ... •Doesn’t
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Lipid Mediators: Synthesis,Lipid Mediators: Synthesis,Metabolism, and FunctionMetabolism, and Function
Biochemistry 201Oct 23, 2007Electa Park
OverviewOverview
• Biological function of lipid mediators• Arachidonic acid (AA) synthesis• AA metabolites and related enzymes
• Reduce body temperature in febrile states– Analgesic
• Low to moderate pain caused by inflammation
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AcetominophenAcetominophen
• Analgesic• Antiinflammatory• Not antipyrogenic• Doesn’t inhibit COX1/2; may inhibit COX3• No longer considered an NSAID• Hepatotoxicity when combined with alcohol
– Glutathione depletion
Inhibitors of PG SynthesisInhibitors of PG Synthesis• COX inhibitors-
• Mechanism of action:– Selectively inhibits COX-2COX-2 which is induced locally at
the site of inflammation– Does not interfere with constitutive form that protects
the gastrointestinal tract– Drug companies thought they had a safer drug to
treat forms of osteoarthritis• Vioxx recall-
– COX-2 metabolites improtant for platelet deaggregationand vascular healing
– Major cardiovascular complications» Heart attack» Stroke
COX-2 InhibitorsCOX-2 Inhibitors
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Merck Announces Voluntary WorldwideWithdrawal of VIOXX®WHITEHOUSE STATION, N.J., Sept. 30, 2004—Merck & Co., Inc. today announced a voluntaryworldwide withdrawal of VIOXX® (rofecoxib), its arthritis and acute pain medication.The company’s decision, which is effective immediately, is based on new, three-year data from a prospective, randomized, placebo-controlled clinical trial, theAPPROVe (Adenomatous Polyp Prevention on VIOXX) trial.
PLA2
Arachidonic Acid
Prostaglandins Leukotrienes
Prostacyclin Thromboxanes
COX 1/2 lipoxygenase
PAF
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Platelet Activating FactorPlatelet Activating Factor• Lipid mediator derived from
phosphatidylcholine• Platelet and leukocyte activation
• Peptidase activity• Make compounds less hydrophobic →
excretion in urine
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ReferencesReferences• Phospholipases
– Diaz BL, JP Arm Phospholipase A2, Prostaglands Leukot and Essent FattyAcids 69 (2003) 87-97
– Dessen A Structure and Mechanism of human cytosolic phospholipase A2,Biochim Biophys Acta 1488 (2000) 40-47
• COX1/2 & PGs– Rouzer CA, LJ Marnett Structural and functional differences between
cyclooxygenases: Fatty acid oxygenases with a critical role in cell signalingBiochem Biophys Res Comm 338 (2005) 34-44
– Smith WL, I Song The enzymology of prostaglandin endoperoxide H synthases1- and 2, Prostaglands other lipid mediat 68-69 (2002) 115-128
– Garavito RM, MG Malkowski, DL DeWitt the structures of prostaglandinendoperoxide H synthases-1 and -2, Prostaglanding other lipid mediat 68-69(2002) 129-152
– Gupta K, BS Selinsky, CJ Kaub, AK Katz, PJ Loll The 2.0 A Resolution CrystalStructure of Prostaglandin H2 Synthase-1: Structural Insights into an UnusualPeroxidase, J Mol Biol 335 (2004) 503-518
• Thromboxane– Wang L-H, RJ Kulmacz Thromboxane synthase: structure and function of
protein and gene Prostaglandins other lipid mediat 68-69 (2002) 409-422
• Lipoxygenases and LTs– Murphy RC, MA Gijon Biosynthesis and metabolism of leukotrienes Biochem J
405 (2007) 379-395• PAF
– Prescott SM, GA Zimmerman, DM Stafforini, TM McIntyre Platelet-ActivatingFactor and Related Lipid Mediators Annu Rev Biochem 69 (2000) 419-445
• Inhibitors– Bertolini A, A Ottani, M Sandrini Selective COX-2 Inhibitors and Dual Acting
Anti-inflammatory Drugs: Critical Remarks Curr Med Chem 9 (2002) 1033-1043– Rajakariar R, MM Yaqoob, DW Gilroy COX-2 in Inflammation and Resolution
Mol Interv 6 (2006) 199-207• Receptors
– Narumiya S Prostanoid Receptors: Structure, Function, and Distribution Ann NY Acad Sci 744 (1994) 126-138
• CYP 450– Kalsotra A, HW Strobel Cytochrome P45 4F subfamily: At the crossroads of
eicosanoid and drug metabolism Pharmacol Ther 112 (2006) 589-611• PG/LT/TX function
– Miller SB Prostaglandins in Health and Disease: An overview J Semarthrit 3(2006) 37-49
– William KI, GA Higgs Eicosanoids and Inflammation J Pathol 156 (1988) 101-110