Lipoxygenase Enzyme Mechanisms in Arachidonic Acid Metabolism

Lipoxygenases are non-haem iron enzymes that catalyse the regio- and stereo-specific oxygenation of arachidonic acid through a radical mechanism. The reaction proceeds via abstraction of a bis-allylic hydrogen atom to form a pentadienyl radical, followed by insertion of molecular oxygen at a defined carbon and reduction to yield hydroperoxy eicosatetraenoic acids. Isoforms such as 5-, 12- and 15-lipoxygenase differ in active-site geometry and substrate orientation, determining product specificity. An N-terminal C2-like domain mediates calcium-dependent membrane binding, directing subcellular localisation and access to membrane-released arachidonic acid. The resulting hydroperoxy intermediates give rise to diverse bioactive lipids, including leukotrienes that amplify inflammatory responses and specialised pro-resolving mediators that facilitate the resolution phase. Dysregulated lipoxygenase activity contributes to pathologies such as atherosclerosis, asthma and metabolic inflammation, underscoring the therapeutic potential of selective isoform modulation.

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Lipoxygenase Enzyme Mechanisms in Arachidonic Acid Metabolism publication trend

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Technical terms

Arachidonic Acid: A 20-carbon polyunsaturated fatty acid that serves as the principal substrate for lipoxygenase-catalysed oxidation.

Lipoxygenases (LOXs): A family of non-haem iron enzymes that stereospecifically insert molecular oxygen into polyunsaturated fatty acids to form hydroperoxy derivatives.

Hydroperoxy Derivatives: Initial oxygenated products of LOX activity, often reduced to hydroxy eicosatetraenoic acids (HETEs) or converted into downstream mediators.

Eicosanoids: Bioactive lipid mediators derived from arachidonic acid via LOX, cyclooxygenase or cytochrome P450 pathways, including leukotrienes and HETEs.

Specialised Pro-Resolving Mediators (SPMs): Lipid compounds derived from LOX products that actively orchestrate the resolution of inflammation.

References

1. Knock-in mice expressing a humanized arachidonic acid 15-lipoxygenase (Alox15) carry a partly dysfunctional erythropoietic system. Cellular & Molecular Biology Letters (2023).
2. 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 (2023).
3. Regulation and Functions of 15-Lipoxygenases in Human Macrophages. Frontiers in Pharmacology (2019).
4. Lipoxygenases: Occurrence, Functions, Catalysis, and Acquisition of Substrate*. Journal of Biological Chemistry (1999).
5. Molecular Basis of the Specific Subcellular Localization of the C2-like Domain of 5-Lipoxygenase∗. Journal of Biological Chemistry (2002).
6. Applicability of the Triad Concept for the Positional Specificity of Mammalian Lipoxygenases*. Journal of Biological Chemistry (2009).