Stereochemistry and Mechanism of the Biosynthesis of Leukotriene A4 from 5(S)-Hydroperoxy-6(E),8,11,14(Z)-eicosatetraenoic Acid. Evidence for an Organoiron Intermediate

Article abstract of DOI:10.1021/ja00186a046

The pathway of biosynthesis of leukotriene A₄ (LTA₄, 2) from 5(S)-hydroperoxy-6(E),8,11,14(Z)-eicosatetraenoic acid (5-S-HPETE, 1) has been explored by the comparative study of (S)- and (R)-lipoxygenase (LO) enzymes as catalysts.The purified LO from potato, an S-lipoxygenase, converts (anaerobically) 1 to 2 (determined as the characteristic hydrolysis mixture of two epimeric 5,6-diols and two epimeric 5,12-diols), as previously reported by Samuelsson et al.However, the 8-R-LO from the coral Plexaura homomalla transforms 1 (anaerobically) into 6-epi-LTA₄ (6).Theobserved divergence of stereopathways agrees with predictions based on the intermediacy of organoiron intermediates in enzymic lipoxygenation (Scheme I) and detailed in Schemes II and III.Further evidence for the intervention of such intermediates has been obtained by trapping experiments under pure O2 at pressures of 1-60 atm.Under O2 pressure 1 is converted by the potato LO to a new product, the bis(hydroperoxide) 7, whereas the coral LO converts 1 to the diastereomeric bis(hydroperoxide) 9.