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Edited by Klaus van Leyen, Harvard Medical School, Charlestown, MA, and accepted by Editorial Board Member Ruslan Medzhitov May 27, 2016 (received for review March 10, 2016)
Significance
Lipoxygenases are lipid-peroxidizing enzymes that have been classified according to their reaction specificity. ALOX15 (12/15-lipoxygenase) has been implicated in inflammatory resolution via biosynthesis of antiinflammatory and proresolving lipoxins. We found that lower mammals including lower primates express arachidonic acid 12-lipoxygenating ALOX15 orthologs, whereas higher primates express 15-lipoxygenating enzymes. Gibbons constitute the missing link interconnecting 12- and 15-lipoxygenating ALOX15 orthologs. To explore the evolutionary driving force for this specificity alteration, we quantified the lipoxin synthase activity of 12- and 15-lipoxygenating ALOX15 orthologs and observed that the lipoxin synthase activities of 15-lipoxygenating enzymes were significantly higher. These results suggest an evolution of ALOX15 specificity, which optimizes the biosynthetic capacity for antiinflammatory and proresolving lipoxins.
Abstract
ALOX15 (12/15-lipoxygenase) orthologs have been implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids. Here we hypothesized that lower mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologs. In contrast, 15-lipoxygenating isoforms are found in higher primates (orangutans, men), and these results suggest an evolution of ALOX15 specificity. To test this hypothesis we first cloned and characterized ALOX15 orthologs of selected Catarrhini representing different stages of late primate evolution and found that higher primates (men, chimpanzees) express 15-lipoxygenating orthologs. In contrast, lower primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity. To explore the driving force for this evolutionary alterations, we quantified the lipoxin synthase activity of 12-lipoxygenating (rhesus monkey, mouse, rat, pig, humIle418Ala) and 15-lipoxygenating (man, chimpanzee, orangutan, rabbit, ratPhe353Ala) ALOX15 variants and found that, when normalized to their arachidonic acid oxygenase activities, the lipoxin synthase activities of 15-lipoxygenating ALOX15 variants were more than fivefold higher (P < 0.01). Comparative molecular dynamics simulations and quantum mechanics/molecular mechanics calculations indicated that, for the 15-lipoxygenating rabbit ALOX15, the energy barrier for C13-hydrogen abstraction (15-lipoxygenation) was 17 kJ/mol lower than for arachidonic acid 12-lipoxygenation. In contrast, for the 12-lipoxygenating Ile418Ala mutant, the energy barrier for 15-lipoxygenation was 10 kJ/mol higher than for 12-lipoxygenation. Taken together, our data suggest an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins.
Footnotes
↵1S.A. and F.K. contributed equally to this work.
↵2Present address: Institute of Biotechnology, RWTH Aachen University, 52074 Aachen, Germany.
- ↵3To whom correspondence should be addressed. Email: hartmut.kuehn{at}charite.de.
Author contributions: S.A., F.K., T.H., H.K., and D.H. designed research; S.A., F.K., À.G.-L., M.P., P.S., L.M., J.M.L., S.S., H.K., and D.H. performed research; S.A., F.K., À.G.-L., M.P., P.S., L.M., J.M.L., S.S., H.K., and D.H. analyzed data; and S.A., À.G.-L., T.H., H.K., and D.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. K.v.L. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1604029113/-/DCSupplemental.
Mammalian ALOX15 evolution
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