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Manganese lipoxygenase (Mn-LOX) catalyzes the rearrangement of bis-allylic Shydroperoxides to allylic R-hydroperoxides, but little is known about the reaction mechanism. 1-Linoleoyl-lysoglycerophosphatidylcholine was oxidized in analogy with 18:2n-6 at the bis-allylic carbon with rearrangement to C-13 at the end of lipoxygenation, suggesting a "tail-first" model. The rearrangement of bis-allylic hydroperoxides was influenced by double bond configuration and the chain length of fatty acids. The Gly316Ala mutant changed the position of lipoxygenation toward the carboxyl group of 20:2n-6 and 20:3n-3 and prevented the bis-allylic hydroperoxide of 20:3n-3 but not 20:2n-6 to interact with the catalytic metal. The oxidized form, Mn III -LOX, likely accepts an electron from the bis-allylic hydroperoxide anion with the formation of the peroxyl radical, but rearrangement of 11-hydroperoxyoctadecatrienoic acid by Mn-LOX was not reduced in D 2 O (pD 7.5), and aqueous Fe 3+ did not transfer 11S-hydroperoxy-9Z, 12Z, 15Z-octadecatrienoic add to allylic hydroperoxides. Mutants in the vicinity of the catalytic metal, Asn466Leu and Ser469Ala, had little influence on bis-allylic hydroperoxide rearrangement.jlr In conclusion, Mn-LOX transforms bis-allylic hydroperoxides to allylic by a reaction likely based on the positioning of the hydroperoxide close to Mn 3+ and electron transfer to the metal, with the formation of a bis-allylic peroxyl radical, β-fragmentation, and oxygenation under steric control by the protein.-Oliw, E. H. Factors influencing the rearrangement of bis-allylic hydroperoxides by manganese lipoxygenase.