Factors influencing the rearrangement of bis-allylic hydroperoxides by manganese lipoxygenase

Ernst H. Oliw

Dept of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden SE-751 24

Corresponding Author: ernst.oliw{at}farmbio.uu.se

Manganese lipoxygenase (Mn-LOX) catalyzes rearrangement of bis-allylic S hydroperoxides 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 chain length of fatty acids. The Gly316Ala mutant changed the position of lipoxygenation towards 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, MnIII-LOX, likely accepts an electron from the bis-allylic hydroperoxide anion with formation of the peroxyl radical, but rearrangement of 11-HPOTrE by Mn-LOX was not reduced in D2O (pD 7.5) and aqueous Fe3+ did not transfer 11S-hydroperoxy-9Z,12Z,15Z-octadecatrienoic acid to allylic hydroperoxides. Mutants in the vicinity of the catalytic metal, Asn466Leu and Ser 469Ala, had little influence on bis-allylic hydroperoxide rearrangement. In conclusion, Mn-LOX transforms bis-allylic hydroperoxides to allylic by a reaction likely based on positioning of the hydroperoxide close to Mn3+ and electron transfer to the metal with formation of a bis-allylic peroxyl radical, ß-fragmentation, and oxygenation under steric control by the protein.

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