ArticleProceedings of the National Academy of Sciences of the United States of America2016
Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 69 citations in OpenAlex.
- Paratuberculosis vaccination induces a phenotype consistent with trained immunity in bovine neutrophils.NPJ vaccines · 2026Article
- Recent advances in thiazole-based derivatives targeting diverse anti-inflammatory pathways.RSC advances · 2026Review
- Oxidative Stress Mediated by Macrophages Promotes Angiogenesis and Early Development of Endometriosis.Antioxidants (Basel, Switzerland) · 2026Article
- The role of ALOX15 in inflammation-related diseases.Frontiers in immunology · 2026Review
- Functional humanization of 15-lipoxygenase-1 (Alox15) protects mice from dextran sodium sulfate induced intestinal inflammation.Cellular & molecular biology letters · 2025Article
- Expression and clinical significance of the p53/SAT1/ALOX15 ferroptosis-associated proteins in sinonasal inverted papilloma.World journal of otorhinolaryngology - head and neck surgery · 2025Article
- Murine Alox8 versus the human ALOX15B ortholog: differences and similarities.Pflugers Archiv : European journal of physiology · 2024Review
- Structural and Functional Biology of Mammalian ALOX Isoforms with Particular Emphasis on Enzyme Dimerization and Their Allosteric Properties.International journal of molecular sciences · 2024Review
- Knock-in mice expressing a humanized arachidonic acid 15-lipoxygenase (Alox15) carry a partly dysfunctional erythropoietic system.Cellular & molecular biology letters · 2023Article
- Dysregulation of humoral immunity, iron homeostasis, and lipid metabolism is associated with multiple sclerosis progression.Multiple sclerosis and related disorders · 2023Article
- Bony Fish Arachidonic Acid 15-Lipoxygenases Exhibit Different Catalytic Properties than Their Mammalian Orthologs, Suggesting Functional Enzyme Evolution during Vertebrate Development.International journal of molecular sciences · 2023Article
- Synthesis of new multitarget-directed ligands containing thienopyrimidine nucleus for inhibition of 15-lipoxygenase, cyclooxygenases, and pro-inflammatory cytokines.European journal of medicinal chemistry · 2023Article
- Transgenic mice overexpressing human ALOX15 under the control of the aP2 promoter are partly protected in the complete Freund's adjuvant-induced paw inflammation model.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2023Article
- Different Structures-Similar Effect: Do Substituted 5-(4-Methoxyphenyl)-1Molecules (Basel, Switzerland) · 2023Article
- Specialized Pro-Resolving Lipid Mediators: Endogenous Roles and Pharmacological Activities in Infections.Molecules (Basel, Switzerland) · 2023Review
- Polyunsaturated Fatty Acids: Conversion to Lipid Mediators, Roles in Inflammatory Diseases and Dietary Sources.International journal of molecular sciences · 2023Review
- Functional Characterization of Transgenic Mice Overexpressing Human 15-Lipoxygenase-1 (ALOX15) under the Control of the aP2 Promoter.International journal of molecular sciences · 2023Article
- Functional Characterization of Novel Bony Fish Lipoxygenase Isoforms and Their Possible Involvement in Inflammation.International journal of molecular sciences · 2022Article
- Arachidonate 15-lipoxygenase type B: Regulation, function, and its role in pathophysiology.Frontiers in pharmacology · 2022Review
- The Reaction Specificity of Mammalian ALOX15 Orthologs is Changed During Late Primate Evolution and These Alterations Might Offer Evolutionary Advantages for Hominidae.Frontiers in cell and developmental biology · 2022Article
Corrections and comments
- Erratum issued
- Erratum issued
Authors and funding
11 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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, ratLeu353Phe) 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) [corrected]. 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.
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