title: Investigation of the chemical conversion of hydroperoxyeicosatetraenoate to leukotriene epoxide using stereospecifically labeled arachidonic acid. Comparison with the enzymatic reaction.
abstract: A series of stereospecifically labeled polyunsaturated fatty acids were prepared by biosynthesis from [8-DR-3H]- and [8-LS-3H]stearic acids. The labeled stearic acids were synthesized by a novel scheme employing readily available alkyne and aldehyde starting materials. The stereochemical purity of the prochiral tritium labels was judged to be greater than 99%, as determined by analysis of the octadec-1-yn-8(R)- and 8(S)-ol intermediates in the synthesis. Previously, the labeled arachidonic acids were used to investigate the stereoselectivity of hydrogen abstraction in the biosynthesis of leukotriene epoxides. We have now investigated the selectivity of hydrogen abstraction in a chemical synthesis of 14,15-leukotriene (LT) A4 from mixtures of [3-14C]- and either [10-DR-3H]- or [10-LS-3H]15(S)-HPETE methyl esters. Reaction with either chirally labeled precursor led to 70-95% retention of 3H relative to 14C in the 14,15-LTA4 and 10-Z-14,15-LTA4 products after purification by high performance liquid chromatography. The 15-dienone obtained from this reaction was consistently enriched in 3H relative to 14C after isolation and purification. Evidence was obtained to indicate that the majority of the 3H in the products was retained in its original location and configuration. These results indicate that the biomimetic chemical reaction is stereo-random with respect to hydrogen loss from carbon 10 and that, in contrast to the reaction as it occurs in leukocytes and platelets, in the chemical model the reaction begins by decomposition of the hydroperoxide group, with hydrogen loss from carbon 10 occurring as a late or final step.
authors.forename: R L
authors.initials: RL
authors.lastname: Maas
authors.forename: C D
authors.initials: CD
authors.lastname: Ingram
authors.forename: A T
authors.initials: AT
authors.lastname: Porter
authors.forename: J A
authors.initials: JA
authors.lastname: Oates
authors.forename: D F
authors.initials: DF
authors.lastname: Taber
authors.forename: A R
authors.initials: AR
authors.lastname: Brash
mesh_terms: D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006859:Hydrogen / Q000378:metabolism; D017572:Leukotriene A4; D015289:Leukotrienes; D008054:Lipid Peroxides / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
chemical_list: D001095:Arachidonic Acids; D017572:Leukotriene A4; D015289:Leukotrienes; D008054:Lipid Peroxides; D016718:Arachidonic Acid; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; C025348:arachidonic acid 5-hydroperoxide; D006859:Hydrogen