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Lipoxygenase

Lipoxygenases (LOXs) are a family of non-heme iron-containing dioxygenases that catalyze the stereospecific oxygenation of polyunsaturated fatty acids, such as arachidonic acid and linoleic acid, by inserting molecular oxygen to form hydroperoxy derivatives like 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and 15-hydroperoxyeicosatetraenoic acid (15-HPETE).^[1] These hydroperoxides act as precursors for bioactive lipid mediators, including leukotrienes, lipoxins, hepoxilins, and hydroxy fatty acids, which are essential for regulating inflammation, immune responses, and cellular signaling.^[2] The catalytic mechanism relies on a ferric iron (Fe³⁺) cofactor, where inactive ferrous iron (Fe²⁺) is activated by lipid hydroperoxides, enabling the enzyme's role in lipid peroxidation pathways.^[3] In mammals, lipoxygenases are encoded by six functional genes in humans—ALOX5 (5-LOX), ALOX12 (12-LOX), ALOX15 (15-LOX-1), ALOX15B (15-LOX-2), ALOX12B (12R-LOX), and ALOXE3 (epidermal LOX-3)—with most located on chromosome 17 except ALOX5 on chromosome 10; mice possess seven isoforms.^[2] These isoforms exhibit tissue-specific expression and positional specificity, determining the carbon atom where oxygenation occurs (e.g., 5-LOX at position 5, 12-LOX at position 12), and are found across kingdoms including plants, fungi, and bacteria, where they contribute to development, stress responses, and pathogen defense.^[1] For instance, 5-LOX predominates in immune cells like leukocytes, while 12R-LOX and eLOX-3 are expressed in skin epithelial cells.^[3] Lipoxygenases play pivotal roles in physiology and pathophysiology, influencing cell proliferation, differentiation, redox homeostasis, and membrane remodeling through eicosanoid production.^[2] Dysregulation is implicated in diseases such as asthma (via 5-LOX-derived leukotrienes), atherosclerosis (through 15-LOX-mediated LDL oxidation), cancer (e.g., 12-LOX in tumor progression), skin disorders like ichthyosis (due to 12R-LOX and eLOX-3 mutations), and neurodegeneration.^[1] Their products also promote ferroptosis—a form of iron-dependent cell death—and oxidative stress, highlighting their dual pro- and anti-inflammatory functions in resolving inflammation or exacerbating tissue damage.^[3]

Biochemistry

Definition and general properties

Lipoxygenases (EC 1.13.11.-) constitute a family of non-heme iron-containing dioxygenases that catalyze the stereospecific dioxygenation of polyunsaturated fatty acids (PUFAs), such as arachidonic acid and linoleic acid, to form hydroperoxy derivatives.^[4]^[5] These enzymes require molecular oxygen as a cosubstrate and incorporate one oxygen atom from O₂ into the PUFA substrate at a specific position, with the iron cofactor playing a central role in the oxidative process.^[6] Most lipoxygenase isoforms exhibit molecular weights in the range of 75-100 kDa and are widely distributed across diverse organisms, including plants, animals, fungi, and bacteria.^[7]^[8] This broad occurrence underscores the evolutionary conservation of the lipoxygenase domain, a catalytic unit preserved across prokaryotic and eukaryotic kingdoms, reflecting ancient origins and functional adaptations in lipid metabolism.^[9] The enzyme family was first identified in the 1930s through studies on soybean seeds, where André and Horeau described an activity termed "lipoxidase" that promotes the peroxidation of unsaturated fatty acids.^[10] Mammalian lipoxygenases were subsequently discovered in the mid-1970s, with the initial reports focusing on isoforms in platelets and leukocytes that oxygenate arachidonic acid.^[2]

Catalytic mechanism and kinetics

Lipoxygenases catalyze the regioselective and stereospecific dioxygenation of polyunsaturated fatty acids (PUFAs) with a 1,4-cis,cis-pentadiene moiety, converting them into hydroperoxy derivatives. The reaction proceeds via a radical mechanism initiated by the ferric hydroxide moiety (Fe^III-OH) at the non-heme iron center, which abstracts a hydrogen atom from the bis-allylic methylene group of the substrate through proton-coupled electron transfer (PCET). This step generates a delocalized pentadienyl radical and reduces the iron to the ferrous aquo complex (Fe^II-OH₂).^[11]^[12] The pentadienyl radical then reacts with triplet molecular oxygen, which adds to one terminus of the radical system in a regioselective manner, forming a product peroxyl radical; this oxygen insertion occurs on the face opposite to the initial hydrogen abstraction. Finally, the peroxyl radical is reduced, yielding the hydroperoxy fatty acid product and regenerating the Fe^III state to complete the catalytic cycle. The non-heme iron thus cycles between Fe^II and Fe^III oxidation states, with activation of the resting Fe^II form often requiring hydroperoxy fatty acids as redox cofactors. The overall transformation is summarized by the equation:

\text{PUFA} + \text{O}_2 \rightarrow \text{PUFA-OOH}

For instance, mammalian 5-lipoxygenase converts arachidonic acid to 5-S-hydroperoxyeicosatetraenoic acid (5-HPETE).^[11]^[13]^[14] The hydrogen abstraction is suprafacial with respect to the substrate plane, while oxygenation is antarafacial, ensuring the formation of chiral hydroperoxide products with specific S or R configurations at the oxygenated carbon. This stereochemical relationship has been confirmed using stereospecifically labeled fatty acids, such as those with deuterium or tritium at the reactive methylene, revealing nearly complete retention of configuration during abstraction.^[11]^[15] Lipoxygenases follow Michaelis-Menten kinetics, with K_m values for arachidonic acid typically ranging from 10 to 50 μM in mammalian isoforms like 5-lipoxygenase, reflecting efficient substrate binding at physiological concentrations. V_max varies by isoform and conditions, but catalytic turnover numbers reach approximately 300 s^-1 for well-studied examples such as soybean lipoxygenase-1 and coral 8R-lipoxygenase. The enzymes exhibit pH optima between 7 and 9; for example, plant lipoxygenase-1 optima at pH 8–9, while mammalian 5-lipoxygenase peaks at pH 7.5, aligning with cellular environments where activity is modulated by local pH shifts.^[14]^[11]^[10]

Structure

Three-dimensional architecture

Lipoxygenases share a conserved overall fold comprising two distinct domains: an N-terminal PLAT (polycystin-1, lipoxygenase, α-toxin) domain and a larger C-terminal catalytic domain. The PLAT domain adopts an eight-stranded antiparallel β-barrel structure, which facilitates membrane binding and targeting of the enzyme to lipid bilayers where substrates are abundant. In contrast, the catalytic domain is predominantly α-helical, featuring a bundle of four helices (N-terminal helices I–IV) that form the core, surrounded by additional helices and five antiparallel β-sheets. This architecture is preserved across diverse lipoxygenases from plants, animals, and other organisms, underscoring its evolutionary stability despite sequence variations.^[16] The first high-resolution crystal structures of lipoxygenases were reported in the mid-1990s, revealing this conserved domain organization. Soybean lipoxygenase-1 (LOX-1), a plant enzyme, was solved at 1.4 Å resolution in 1996 (PDB: 1YGE), showing the β-barrel PLAT domain (residues 1–146) connected via a flexible linker to the catalytic domain (residues 147–839). Shortly thereafter, the structure of rabbit reticulocyte 15-lipoxygenase (15-LOX) was determined at 2.1 Å resolution in 1997 (PDB: 1LOX), confirming the similarity to the plant enzyme and identifying the PLAT domain as a common feature in mammalian lipoxygenases. More recently, the crystal structure of human 5-lipoxygenase (5-LOX) was elucidated in 2011 at 2.4 Å resolution (PDB: 3O8Y), further validating the domain architecture while highlighting subtle adaptations in the mammalian isoform.^[16] Lipoxygenases typically function as monomers in solution, but certain isoforms exhibit dimerization through specific interfaces, often involving the catalytic domain's helical regions or the PLAT domain, which can modulate stability and activity. For instance, human 5-LOX forms dimers under physiological conditions, with the interface mediated by hydrophobic interactions at the N-terminal helices. Oligomeric states vary by isoform and environmental factors, such as ionic strength, with some lipoxygenases assembling into higher-order oligomers like tetramers or hexamers in membrane environments.^[17]^[18] This structural conservation persists despite relatively low sequence identity of approximately 20–30% between lipoxygenases from distant species, such as plants and mammals, enabling functional divergence while maintaining the core scaffold essential for catalysis. Comparative analyses of these structures highlight invariant elements, including the positioning of the PLAT domain relative to the catalytic core, which supports membrane recruitment across evolutionary lineages.^[16]^[19]

Active site features

The active site of lipoxygenases centers on a non-heme iron atom that cycles between Fe(II) and Fe(III) oxidation states during catalysis. In the well-studied soybean lipoxygenase-1 (LOX-1), the iron is coordinated in an octahedral geometry by the nitrogen atoms of three conserved histidine residues (His499 Nδ, His504 Nε, and His690 Nε), the oxygen atom of asparagine (Asn694 Oδ), the carboxylate oxygen of the C-terminal isoleucine (Ile839), and a water molecule.^[20]^[21] This coordination sphere positions the iron deep within the protein, approximately 15–20 Å from the surface, facilitating substrate activation while maintaining redox flexibility; mutations such as His499Ala or His504Ala disrupt iron binding and abolish enzymatic activity.^[20] Spectroscopic studies, including electron paramagnetic resonance (EPR) and Mössbauer spectroscopy, confirm the high-spin Fe(III) state in the resting enzyme (S = 5/2), with EPR revealing characteristic g-values around 6.0, 4.3, and 2.0 indicative of a distorted octahedral environment, while Mössbauer data support the ligand assignments and detect subtle changes upon reduction to Fe(II).^[22]^[23] The substrate-binding channel leading to the iron active site is a narrow, hydrophobic pocket extending approximately 25 Å from the protein surface, lined primarily by nonpolar residues such as leucines, valines, and phenylalanines that accommodate the polyunsaturated fatty acid chain.^[24] Specificity for positional oxygenation is governed by steric determinants within this channel, including small residues like glycine (e.g., Gly523 in soybean LOX-1 homologs) that permit deeper tail insertion for ω-end attack, versus bulkier valine or isoleucine residues that restrict access and favor α-end positioning; site-directed mutagenesis of these residues, such as Gly to Val, shifts product profiles from 13- to 9-hydroperoxy derivatives in linoleate substrates.^[25] Recent high-resolution cryo-electron microscopy (cryo-EM) structures of full-length, membrane-bound human 12S-lipoxygenase (12-LOX) at 1.7–2.8 Å resolution reveal conserved channel features in the lipid bilayer context, with the iron site embedded in a helical bundle and the binding pocket oriented for membrane substrate access.^[26]

Classification

Positional and stereospecific types

Lipoxygenases are classified based on their positional specificity, which refers to the carbon atom on the fatty acid substrate where molecular oxygen is inserted to form the hydroperoxide product. In mammals, common types include 5-lipoxygenase (5-LOX), which oxygenates arachidonic acid at the C5 position; 12-lipoxygenase (12-LOX), acting at C12; and 15-lipoxygenase (15-LOX), targeting C15.^[6] Other variants such as 8-LOX and 11-LOX oxygenate at C8 and C11, respectively, though less prevalent. In plants, positional specificity is typically defined using linoleic acid as substrate, yielding 9-LOX at C9 or 13-LOX at C13.^[27] Stereospecificity describes the chirality (S or R configuration) at the hydroperoxide carbon in the product. Mammalian lipoxygenases predominantly produce the S enantiomer, such as (S)-5-hydroperoxyeicosatetraenoic acid (5-HPETE) from 5-LOX or (S)-15-HPETE from 15-LOX. In contrast, plant lipoxygenases exhibit more variability, with many forming S-hydroperoxides like (13S)-hydroperoxyoctadecadienoic acid (13S-HPODE), though some isoforms can generate R products. Certain mammalian enzymes, like 12R-LOX, specifically yield the R configuration at C12.^[6]^[27] Some lipoxygenases display dual positional specificity, producing mixtures of products depending on conditions like pH or substrate orientation. For instance, certain plant isoforms function as 9/13-LOX, generating both 9-HPODE and 13-HPODE from linoleic acid, often in ratios influenced by the enzyme's active site flexibility.^[27] This classification aligns with Enzyme Commission (EC) numbering under EC 1.13.11.- for lipoxygenases. Specific examples include EC 1.13.11.34 for arachidonate 5-lipoxygenase, EC 1.13.11.31 for the 12S variant, and EC 1.13.11.33 for arachidonate 15-lipoxygenase. In plants, linoleate 13S-lipoxygenase is designated EC 1.13.11.12.^[28]^[29]^[30] Biochemical assays confirm positional and stereospecific types through product analysis. Reverse-phase high-performance liquid chromatography (RP-HPLC) separates positional isomers based on retention times, while chiral phase HPLC resolves enantiomers to determine S/R configuration, often after enzymatic reduction of hydroperoxides to hydroxy acids for better resolution.^[31]

Isoforms across organisms

Lipoxygenases (LOXs) are encoded by multigene families across various organisms, with isoforms exhibiting distinct substrate specificities and expression patterns. In plants, particularly Arabidopsis thaliana, the genome contains six LOX genes (LOX1 through LOX6), which are classified based on their positional specificity for oxygenation of polyunsaturated fatty acids. LOX1 and LOX5 encode 9-LOX isoforms that primarily oxygenate linoleic acid at the 9-position, while LOX2, LOX3, LOX4, and LOX6 are 13-LOX isoforms that act at the 13-position. For instance, LOX2 is prominently expressed in response to wounding and jasmonic acid signaling, contributing to defense mechanisms.^[32]^[33]^[34] In mammals, LOX isoforms are similarly diverse, with humans possessing six functional genes: ALOX5 (encoding 5-LOX), ALOX12 (12-LOX), ALOX15 (15-LOX), ALOX15B (also known as 15-LOX-2), ALOX12B (12R-LOX), and ALOXE3 (epidermal LOX). These genes are clustered on chromosome 17, except for ALOX5, which resides on chromosome 10. The ALOX5 gene spans approximately 71.9 kb and consists of 14 exons, encoding a protein that is calcium-dependent for membrane translocation and activation. In mice, there are seven functional LOX orthologs: Alox5, Alox12, Alox12b, Alox15, Alox8, Aloxe3, and Aloxe12, which mirror the human isoforms in specificity but show species-specific expression, such as Alox12b in skin epithelia.^[35]^[36]^[37]^[38] Fungal LOXs include specialized isoforms like the 10R-dioxygenase (10R-DOX) in Aspergillus species, such as A. nidulans (encoded by PpoA), which oxygenates linoleic acid to form 10R-hydroperoxyoctadecadienoic acid as part of oxylipin biosynthesis pathways. In bacteria, LOXs are less common but notable in pathogens like Pseudomonas aeruginosa, where the loxA gene encodes a secreted 15-LOX (LoxA) that acts on arachidonic acid, potentially aiding in host immune evasion.^[39]^[40]

Biological Functions

Roles in plants

In plants, lipoxygenases (LOXs) play a central role in the biosynthesis of jasmonic acid (JA), a key oxylipin hormone that mediates wound responses and pathogen defense. The process begins with 13-LOX isoforms oxygenating α-linolenic acid to form 13-hydroperoxylinolenic acid, which is then converted through subsequent enzymatic steps into 12-oxo-phytodienoic acid and ultimately JA.^[41] A chloroplast-localized 13-LOX in Arabidopsis thaliana is essential for wound-induced JA accumulation, highlighting its specificity in initiating the octadecanoid pathway during tissue damage.^[41] In soybean, the 13-LOX isoform GmLOX6 positively regulates JA production under salt stress, enhancing tolerance by coordinating downstream defense signaling.^[42] Similarly, in rice, the LOX gene OsRCI-1 contributes to herbivore-induced JA biosynthesis, balancing plant defense against growth trade-offs.^[43] LOXs also contribute to the formation of flavor and aroma compounds via the 9-LOX pathway, producing green leaf volatiles (GLVs) such as (Z)-3-hexenal from linoleic acid in fruits and vegetables. These C6 aldehydes and alcohols are released upon mechanical damage or during ripening, imparting characteristic "green" scents to crops like cucumber and tomato.^[44] In cucumber, LOXs generate these volatiles, which not only influence sensory quality but also serve as indirect defense signals attracting natural enemies of herbivores.^[45] Recombinant plant 9-LOXs have been used to biosynthesize GLVs, underscoring their efficiency in producing these compounds from polyunsaturated fatty acids.^[46] During plant development, LOXs facilitate lipid mobilization and signaling critical for seed germination and pollen maturation. In rice, the type I LOX OsLOX2 promotes seed germination by degrading storage lipids but inversely affects seed longevity, illustrating its dual regulatory function in early seedling establishment.^[47] Brassica napus seeds predominantly express 13-LOXs acting on free fatty acids during germination, aiding in the breakdown of triacylglycerols to provide energy and carbon skeletons for growth.^[48] In pollen development, Arabidopsis lox3 lox4 double mutants exhibit male sterility due to impaired JA-mediated proliferative arrest in anther tissues, emphasizing LOXs' role in reproductive maturation.^[49] Olive pollen relies on LOX activity alongside lipases for oil body mobilization, ensuring sufficient energy for tube growth and fertilization.^[50] LOXs are integral to plant stress responses, including oxidative bursts triggered by drought or herbivory, where specific isoforms amplify signaling through oxylipin production. In tomato, the isoform TomloxA is upregulated during wounding and pathogen challenge, contributing to JA-dependent defenses against herbivores.^[51] Under drought, pepper CaLOX1 enhances osmotic stress tolerance by modulating membrane lipid peroxidation and JA levels, with transgenic overexpression improving survival rates.^[52] In melon, CmLOX10 positively regulates drought tolerance via JA signaling, as knockdown lines show reduced root growth and heightened sensitivity.^[53] For herbivory, Arabidopsis LOX2 drives defense against caterpillars by initiating oxylipin bursts that activate antinutritional protein expression.^[54]

Roles in mammals

In mammals, lipoxygenases (LOXs) play crucial roles in eicosanoid-mediated signaling and maintenance of physiological homeostasis, particularly through the metabolism of arachidonic acid into bioactive lipids that regulate immune responses and tissue integrity. The 5-LOX isoform is predominantly expressed in leukocytes, where it catalyzes the initial oxygenation of arachidonic acid to form 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is subsequently converted into leukotriene A4 (LTA4). LTA4 serves as a precursor for leukotriene B4 (LTB4), a potent chemoattractant that promotes neutrophil migration and activation at sites of inflammation, facilitating immune cell recruitment and phagocytosis. Additionally, LTA4 can be hydrolyzed by LTA4 hydrolase or conjugated with glutathione by LTC4 synthase to produce cysteinyl leukotrienes (LTC4, LTD4, and LTE4), which induce smooth muscle contraction, including bronchoconstriction in the airways, thereby contributing to vascular permeability and airway tone regulation during host defense.^[55]^[56] Another key physiological function involves the transcellular biosynthesis of lipoxins (LXs), anti-inflammatory mediators derived from collaborative LOX activities across cell types. In this pathway, 15-LOX, often expressed in epithelial and endothelial cells, oxygenates arachidonic acid at the 15-position to form 15-hydroperoxyeicosatetraenoic acid (15-HPETE), which is then transferred to neighboring leukocytes containing 5-LOX. The 5-LOX further metabolizes 15-HPETE into lipoxin A4 (LXA4) and lipoxin B4 (LXB4), or aspirin-acetylated cyclooxygenase-2 can initiate analogous 15-epi-LX formation. These lipoxins actively promote the resolution of inflammation by inhibiting leukocyte recruitment, stimulating monocyte phagocytosis of apoptotic cells, and counteracting pro-inflammatory cytokines, thus restoring tissue homeostasis without immunosuppression.^[57]^[58] In platelets, 12-LOX (encoded by ALOX12) generates 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which is reduced to 12-hydroxyeicosatetraenoic acid (12-HETE), a lipid that enhances platelet aggregation and dense granule secretion in response to agonists like thrombin and collagen. This process supports primary hemostasis by stabilizing platelet plugs at vascular injury sites, preventing excessive bleeding while modulating thrombus formation. Studies in platelet-specific 12-LOX-deficient mice demonstrate impaired aggregation and prolonged tail bleeding times, underscoring its essential role in normal coagulation.^[59]^[60] Epidermal LOXs, including ALOXE3 (epidermis-type LOX-3), ALOX12B (12R-LOX), and ALOX15B (15-LOX type B), are vital for skin barrier formation during keratinocyte differentiation. These enzymes sequentially process ultra-long-chain ω-hydroxyceramides and free fatty acids in corneocytes, releasing esterified lipids that covalently bind to the cornified envelope, forming the water-impermeable lipid barrier that prevents transepidermal water loss and pathogen entry. Deficiency in ALOX12B or ALOXE3 disrupts this lipid processing, leading to unbound corneocyte lipid envelopes and impaired barrier acquisition in mouse models. ALOX15B contributes similarly by generating hepoxilins that aid in lipid mobilization within the stratum granulosum.^[61]^[62]^[63] Mouse models further illuminate these roles, revealing context-dependent impacts on reproduction and hemostasis. Alox15 knockout mice exhibit normal fertility under basal conditions but rescue subfertility in models of oxidative stress, such as heterozygous Gpx4 mutants, by reducing lipid peroxidation in spermatozoa and improving capacitation, highlighting 15-LOX's involvement in male germ cell homeostasis.^[64]^[65] Platelet 12-LOX deficiency exacerbates pulmonary inflammation and worsens outcomes in SARS-CoV-2 infection models, indicating its broader role in modulating inflammatory homeostasis via oxylipin production like 12-HETrE.^[66]

Physiological and Pathological Roles

Involvement in inflammation and immunity

Lipoxygenases play a pivotal role in mammalian inflammation and immunity through the production of bioactive lipid mediators derived from arachidonic acid. The 5-lipoxygenase (5-LOX) isoform is central to pro-inflammatory responses, catalyzing the formation of leukotriene B4 (LTB4), a potent chemoattractant that recruits neutrophils to sites of infection and injury.^[67] LTB4 enhances neutrophil adhesion, migration, and activation, amplifying acute inflammatory cascades in conditions such as infections.^[68] Additionally, 5-LOX generates cysteinyl leukotrienes (LTC4, LTD4, LTE4), which promote bronchoconstriction, vascular permeability, and eosinophil recruitment, contributing to allergic responses and asthma exacerbations.^[69] These mediators are particularly elevated during allergen challenges, underscoring their role in type 2 immune reactions.^[70] In contrast, the resolution phase of inflammation involves 12/15-LOX and 15-LOX isoforms, which produce specialized pro-resolving mediators like lipoxins (LXs) and resolvins that actively dampen excessive immune responses. Lipoxins, such as LXA4, inhibit neutrophil transmigration and promote macrophage efferocytosis, thereby limiting tissue damage.^[71] Resolvins derived from 15-LOX pathways similarly counter pro-inflammatory signals by modulating cytokine production and enhancing regulatory T-cell activity. A 2024 study demonstrated that lymphatic 15-LOX expression promotes resolution in lymphedema by increasing T-regulatory cell populations and reducing persistent inflammation.^[72] Lipoxygenase expression is tightly regulated in immune cells to fine-tune these processes. 5-LOX is predominantly expressed in mast cells and basophils, where it drives leukotriene release upon activation by allergens or pathogens.^[73] Meanwhile, 12/15-LOX isoforms are highly expressed in macrophages, supporting the shift from pro-inflammatory M1 to pro-resolving M2 phenotypes through lipid mediator synthesis.^[74] Beyond inflammation, lipoxygenases exhibit antiviral potential via lipid peroxidation mechanisms that disrupt viral envelopes. A 2025 study revealed that lipoxygenase activity inhibits replication of severe fever with thrombocytopenia syndrome virus (SFTSV) by generating peroxidized lipids that compromise viral integrity and entry into host cells.^[75] This suggests a broader role in innate antiviral immunity. Leukotriene biosynthesis, particularly via 5-LOX, is regulated by the 5-lipoxygenase-activating protein (FLAP), an integral membrane protein that facilitates substrate presentation and enzyme translocation to the nuclear membrane.^[76] FLAP is essential for efficient leukotriene production in activated leukocytes, providing a key feedback mechanism in inflammatory signaling.^[77]

Associations with diseases

Lipoxygenases (LOXs) play significant roles in numerous diseases, primarily through the production of bioactive lipid mediators such as leukotrienes, hydroxyeicosatetraenoic acids (HETEs), and lipoxins, which modulate inflammation, cell proliferation, and oxidative stress. Dysregulated LOX activity contributes to pathological processes in inflammatory, neoplastic, cardiovascular, neurological, and metabolic disorders, with specific isoforms like 5-LOX, 12-LOX, and 15-LOX implicated in distinct mechanisms.^[78]^[79] In inflammatory diseases, 5-LOX is central to asthma and allergic responses by catalyzing the synthesis of cysteinyl leukotrienes (LTC4, LTD4) and LTB4, which promote bronchoconstriction, mucus secretion, and neutrophil recruitment.^[78] Inhibition of 5-LOX with drugs like zileuton reduces these effects in clinical settings.^[78] Similarly, 12/15-LOX pathways drive chronic inflammation in conditions like atherosclerosis and rheumatoid arthritis, where 12-HETE and 15-HETE enhance monocyte adhesion and cytokine production.^[79] In chronic liver diseases such as non-alcoholic steatohepatitis (NASH) and fibrosis, 5-LOX-derived LTB4 activates hepatic stellate cells, promoting extracellular matrix deposition, while 15-LOX metabolites like 15-HETE correlate with disease progression.^[80] LOXs are associated with various cancers, where they influence tumor growth, metastasis, and angiogenesis. 5-LOX upregulation in colorectal cancer, often linked to Apc mutations, supports tumor progression via leukotriene-mediated inflammation and mast cell infiltration.^[78] 12-LOX (ALOX12) is overexpressed in breast and prostate cancers, with genetic variants like rs9904779 increasing breast cancer risk in certain populations and hypermethylation correlating with poor prognosis.^[81] Conversely, 15-LOX can exert tumor-suppressive effects in colon and prostate cancers by producing 13S-HODE, which induces apoptosis, though its downregulation in advanced stages favors malignancy.^[78] Cardiovascular diseases involve LOX-mediated oxidation of low-density lipoprotein (LDL) and endothelial dysfunction. 15-LOX promotes atherosclerosis by oxidizing LDL in macrophages, leading to foam cell formation in animal models like ApoE knockout mice.^[78] 12-LOX contributes to hypertension and diabetic nephropathy through 12-HETE-induced vascular smooth muscle proliferation and renal fibrosis, with polymorphisms like rs2271316 associated with coronary calcification.^[81]^[79] In diabetes, both type 1 and type 2, 12-LOX upregulation in pancreatic islets exacerbates β-cell destruction and insulin resistance, as evidenced by protection from β-cell destruction in 12-LOX knockout mice.^[79] Neurological disorders highlight LOX involvement in neuroinflammation and neurodegeneration. 5-LOX is elevated in Alzheimer's disease (AD) brains, where it enhances amyloid-β production via γ-secretase activation and tau phosphorylation, increasing AD risk by 1.41- to 1.79-fold through genetic variants like rs4769874.^[82]^[83] 5-LOX inhibitors like zileuton mitigate synaptic loss and glial activation in AD models.^[83] In Parkinson's disease, 5-LOX and its metabolites contribute to dopaminergic neuron loss via excitotoxicity, while 12/15-LOX correlates with oxidative damage in affected brain regions.^[79]^[83] Additionally, 12-LOX variants are linked to schizophrenia and bipolar disorder through altered prefrontal cortex integrity.^[78] Other pathologies include skin disorders, where mutations in 12R-LOX cause autosomal recessive congenital ichthyosis by impairing the epidermal lipid barrier.^[78] In renal diseases like diabetic nephropathy, 12-LOX promotes glomerular injury via inflammatory signaling.^[79] Overall, these associations underscore LOXs as promising therapeutic targets, with isoform-specific inhibitors showing potential in preclinical models across these conditions.^[79]^[80]

Inhibitors and Therapeutics

Natural and synthetic inhibitors

Lipoxygenases (LOXs) are inhibited by a variety of natural compounds, primarily through redox mechanisms that target the enzyme's iron cofactor or by competitive binding to the active site. Flavonoids represent a prominent class of natural inhibitors, with quercetin acting as a potent competitive inhibitor of 5-LOX by undergoing oxidative degradation within the enzyme to form protocatechuic acid, which binds near the iron site and disrupts catalysis.^[84] A 2024 study demonstrated that flavonoid-rich extracts from Artemisia vulgaris, obtained via ultrasound-assisted extraction, exhibit mixed-mode inhibition of LOX activity, increasing the Michaelis constant (Km) from 0.283 µM to 0.435 µM and reducing maximum velocity (Vmax) from 0.22 µM/min to 0.058 µM/min, highlighting their potential as broad-spectrum natural modulators.^[85] Additionally, bioactive peptides derived from protein hydrolysates of sources such as millet grains, insect proteins, and milk proteins serve as LOX inhibitors by acting as radical scavengers or through competitive/non-competitive binding; for instance, the millet-derived peptide EQGFLPGPEESGR shows an IC50 of 84.35 µg/mL against soybean LOX-1, as detailed in a 2023 review.^[86] Plant-derived isoflavones from soy, including genistein and daidzein, function as redox inhibitors of LOX by reducing the active ferric iron to its inactive ferrous state, with genistein displaying an IC50 of 107 µM against soybean LOX-1 and a Ki of 60 µM, thereby preventing hydroperoxide formation and aiding in food preservation by minimizing oxidative off-flavors in soy products.^[87] Synthetic inhibitors of LOXs are classified into redox agents, which chelate the iron cofactor, and competitive inhibitors, which block the substrate-binding channel. Nordihydroguaiaretic acid (NDGA), a classic redox inhibitor, potently suppresses 5-LOX with an IC50 of 0.6 µM by stabilizing the ferrous iron state and exhibits non-selective activity across isoforms.^[88] In contrast, baicalein operates as a competitive substrate channel blocker for 12/15-LOX isoforms, inhibiting human platelet 12-LOX with an IC50 of 0.64 µM and reticulocyte 15-LOX-1 with an IC50 of 1.6 µM.^[89] Zileuton, the only FDA-approved 5-LOX inhibitor, exemplifies isoform selectivity as an iron-chelating redox agent with an IC50 of 0.5 µM against 5-LOX, effectively halting leukotriene biosynthesis without significant impact on 12- or 15-LOX.^[90] For 15-LOX-2 selectivity, PD146176 binds to the leukocyte-type 12/15-LOX active site, disrupting catalysis with high specificity over other isoforms.^[91] Recent advancements from the Redoxoma Center in 2024 identified novel synthetic inhibitors for human 15-LOX-2 via virtual screening, such as compounds 10 and 13, which exhibit mixed-type inhibition (binding both free enzyme and enzyme-substrate complex) with Ki values of 16.4 ± 8.1 μM and 15.1 ± 7.6 μM, respectively, and demonstrate preferential docking to 15-LOX-2 over 5-LOX and 12-LOX.^[92] These binding modes underscore the therapeutic potential of targeting specific LOX isoforms through iron chelation for redox inhibition or channel occlusion for competitive blockade.^[88]

Emerging clinical applications

Zileuton, a 5-lipoxygenase (5-LOX) inhibitor, was approved by the FDA in 1996 for the prophylaxis and chronic treatment of asthma in adults and children over 12 years old.^[93] Masoprocol, another 5-LOX inhibitor, received approval for topical treatment of actinic keratosis, demonstrating efficacy in reducing lesion counts through twice-daily application over 14 to 28 days.^[94] Recent pipeline developments include novel inhibitors of human 15-lipoxygenase-2 (h15-LOX-2) identified through virtual screening by researchers at the Center for Redox Processes in Biomedicine (Redoxoma) in 2024, targeting inflammation-related pathways such as atherosclerosis.^[92] For hyperinflammatory responses akin to severe COVID-19, a 2025 study highlighted 12-lipoxygenase (12-LOX) inhibition as a promising strategy, showing reduced inflammation and improved outcomes in SARS-CoV-2-infected mouse models.^[95] In biotechnology, directed evolution techniques have been applied to engineer lipoxygenase variants, such as those from Enterovibrio norvegicus (EnLOX), enhancing catalytic activity and thermostability for applications in food processing as of 2023.^[96] Key challenges in advancing lipoxygenase inhibitors to clinical use involve achieving isoform selectivity among the six human isoforms to avoid unintended effects, as well as mitigating off-target impacts that could exacerbate side effects.^[97] Combination therapies pairing lipoxygenase inhibitors with cyclooxygenase (COX) blockers are being explored to synergistically address arachidonic acid pathway dysregulation in inflammatory conditions.^[98] Looking ahead, activation of lipoxygenases has shown antiviral potential, with a 2024 study demonstrating their virucidal activity against severe fever with thrombocytopenia syndrome virus (SFTSV) via peroxidation of the viral lipid envelope.^[99] In oncology, a 2024 review emphasized ongoing interest in lipoxygenase inhibitors for prostate cancer trials, noting their role in suppressing tumor progression through isoforms like 5-LOX and 12-LOX while 15-LOX-2 may exert protective effects.^[100] As of October 2025, research on 12-LOX inhibitors, such as VLX-1005, has shown promise in improving glucose homeostasis in models of type 2 diabetes, with phase 2 clinical trials underway for conditions like heparin-induced thrombocytopenia.^[101]^[102]

References

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Lipoxygenases (LOXs) are dioxygenases that catalyze the formation of corresponding hydroperoxides from polyunsaturated fatty acids such as linoleic acid and ...
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Mammalian lipoxygenases and their biological relevance - PMC
Lipoxygenases (LOXs) form a heterogeneous class of lipid peroxidizing enzymes, which have been implicated in cell proliferation and differentiation but also ...
[3]
Lipoxygenase - an overview | ScienceDirect Topics
Lipoxygenase is defined as an enzyme that catalyzes the oxidation of polyunsaturated fatty acids, leading to the production of lipid peroxides and ...
[4]
Lipoxygenases | Enzymes - IUPHAR/BPS Guide to PHARMACOLOGY
The lipoxygenases (LOXs) are a structurally related family of non-heme iron ... EC number. 1.13.11.34 · Arachidonic acid + O2 = LTA4 + H2O. Endogenous ...
[5]
Lipoxygenase - an overview | ScienceDirect Topics
Lipoxygenase is defined as a family of mononuclear non-heme iron enzymes that catalyze the regio- and stereospecific dioxygenation of fatty acids, ...
[6]
Lipoxygenases (E.C. 1.13.11.-) - PMC - NIH
Overview: The lipoxygenases (LOXs) are a structurally related family (ENSFM00250000000705) of non-heme iron dioxygenases that function in the production, and ...
[7]
Molecular enzymology of lipoxygenases - PubMed
Nov 15, 2010 · Although soybean LOX1 was discovered more than 60years ago, the structural biology of these enzymes was not studied until the mid 1990s. In ...Missing: history | Show results with:history
[8]
Bacterial lipoxygenases: Biochemical characteristics, molecular ...
Oct 4, 2022 · LOXs are widely distributed in both eukaryotic and prokaryotic organisms, including humans, animals, plants, fungi and bacteria.
[9]
Evolutionary aspects of lipoxygenases and genetic diversity of ...
In this review we are summarizing the current knowledge on the distribution of lipoxygenases in living single and multicellular organisms
[10]
Legume lipoxygenase: Strategies for application in food industry - Shi
Jun 8, 2020 · In 1932, Audre and Hou found that soybean contains a “lipoxidase” enzyme, which catalyzes the peroxidation of various unsaturated fatty acids.
[11]
Control of oxygenation in lipoxygenase and cyclooxygenase catalysis
In both enzymes, hydrogen abstraction is followed by regioselective oxygen addition on the opposite face of the substrate (an antarafacial relationship between ...
[12]
Understanding the Mechanism of the Hydrogen Abstraction from ...
The proton is transferred to the OH–group oxygen to form water, whereas the electron is transferred from the AA C11–C15 pentadiene moiety to the Fe(III) atom to ...
[13]
https://www.jbc.org/article/S0021-9258(19)55475-8/pdf
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Characterization and separation of the arachidonic acid 5 ... - PubMed
The arachidonyl 5-lipoxygenase had a pH optimum of 7.5 and was 50% maximally active at a Ca2+ concentration of 0.05 mM; the Km for production of 5-HPETE/5-HETE ...<|separator|>
[15]
A 12R-lipoxygenase in human skin: Mechanistic evidence ... - PNAS
With P450s, the hydrogen removal and oxygenation exhibit a suprafacial relationship, often mixed with an element of stereorandom hydrogen abstraction (31, 32).
[16]
The structure of mammalian 15-lipoxygenase reveals similarity to ...
Dec 1, 1997 · Here we report the first structure of a mammalian 15-lipoxygenase. The protein is composed of two domains; a catalytic domain and a previously unrecognized β- ...
[17]
Dimerization of human 5-lipoxygenase - De Gruyter Brill
Human 5-lipoxygenase (5-LO) can form dimers as shown here via native gel electrophoresis, gel filtration chroma- tography and LILBID (laser induced liquid ...
[18]
Cryo-EM structures of human arachidonate 12S-lipoxygenase ... - NIH
Our results showed that 12-LOX can exist in multiple oligomeric states, from monomer to hexamer, which may affect its catalytic activity and membrane ...
[19]
Thirty years with three-dimensional structures of lipoxygenases
In contrast, Fe-lipoxygenases catalyse antarafacial hydrogen abstraction and oxygenation as illustrated by 13S-LOX of F. graminearum (Fg13S-LOX) (Fig. 1C) ...<|control11|><|separator|>
[20]
Crystallographic Determination of the Active Site Iron and ... - PubMed
The ligands identified are His-499, His-504, His-690, Asn-694, and Ile-839, the carboxy-terminal residue. Our previous view that these three histidines are ...
[21]
Crystal Structure of Soybean Lipoxygenase L-1 at 1.4 Å Resolution
The octahedral coordination sphere of the Fe also includes the side chains of His499, His504, His690, and Asn694 as well as the terminal carboxylate of Ile839, ...
[22]
New insights from spectroscopy into the structure/function ...
Spectroscopic properties of the redox-active iron in the active site of plant and mammalian lipoxygenases can now be combined with recent crystal structure ...
[23]
The initial characterization of the iron environment in lipoxygenase ...
It was possible to detect Mössbauer signals in highly concentrated samples of native lipoxygenases containing 57Fe at natural abundance. The spectra obtained ...
[24]
[PDF] Conformational Dynamics of Lipoxygenases and Their Interaction ...
Feb 13, 2024 · Abstract: Lipoxygenases (LOXs) are a family of enzymes that includes different fatty acid oxygenases with a common tridimensional structure.
[25]
The structural basis for specificity in lipoxygenase catalysis - PMC
Lipoxygenase (LOX) enzymes are widely expressed in animals, plants, and fungi, and although also ubiquitous in cyanobacteria, LOX enzymes are quite rarely found ...
[26]
Cryo-EM structures of human arachidonate 12S-lipoxygenase ...
In this study, we used single-particle cryo-electron microscopy to determine high-resolution structures (1.7-2.8 Å) of human 12-LOX.
[27]
Lipoxygenases: Occurrence, functions and catalysis - ScienceDirect
Plant LOXes are classified with respect to their positional specificity of LA oxygenation. LA is oxygenated either at carbon atom 9 (9-LOX) or at C-13 (13 ...
[28]
1.13.11.31 arachidonate 12-lipoxygenase - ENZYME
ENZYME entry: EC 1.13.11.31 ; 12-lipoxygenase · (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = (12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate ; 12-lipoxygenase.
[29]
1.13.11.33 arachidonate 15-lipoxygenase - Expasy - ENZYME
ENZYME entry: EC 1.13.11.33 ; 15-lipoxygenase. arachidonate omega(6) lipoxygenase · (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = (15S)-hydroperoxy-(5Z,8Z,11Z,13E)- ...
[30]
1.13.11.12 linoleate 13S-lipoxygenase - Expasy - ENZYME
A common plant lipoxygenase that oxidizes linoleate and alpha- linolenate, the two most common polyunsaturated fatty acids in plants, by inserting molecular ...
[31]
Analysis of the Stereochemistry of Lipoxygenase-Derived ... - PubMed
A chiral phase HPLC method was developed for the simultaneous determination of the positional and optical isomers of the lipoxygenase-derived ...Missing: stereospecificity classification
[32]
Phytochrome B-mediated activation of lipoxygenase modulates an ...
Jun 10, 2014 · There are six isoforms of LOX in Arabidopsis, and these can be classified as 9-LOXs or 13-LOXs according to the position at which oxygen is ...
[33]
Genome-wide analysis of lipoxygenase gene family in Arabidopsis ...
Sep 6, 2010 · The Arabidopsis genome encodes for six. LOX proteins23 (Table 1). The loci AT1G55020, AT3G45140,. AT1G17420 and AT3G22400 are annotated as LOX1, ...
[34]
Oxylipins Produced by the 9-Lipoxygenase Pathway in Arabidopsis ...
Based on their putative amino acid sequences, LOX1 and LOX5 have been proposed to be 9-LOXs, whereas LOX3 is likely to encode a 13-LOX isoform (Liavonchanka and ...
[35]
Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies
12/15-lipoxygenase (12/15-LOX) is an enzyme, which oxidizes polyunsaturated fatty acids, particularly omega-6 and −3 fatty acids, to generate a number of ...
[36]
Regulation and Functions of 15-Lipoxygenases in Human ... - Frontiers
Jul 3, 2019 · The human genome contains six functional LOX genes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOX5, and ALOXE3) each encoding a distinct LOX enzyme ...
[37]
A) Schematic representation of the human ALOX5 gene coding for 5 ...
5-LO is encoded by the ALOX5 gene that is located on chromosome 10 and comprises 71.9 kb (Fig. 3A). It is divided in 14 exons separated by 13 introns (termed ...<|separator|>
[38]
Regulation of Tissue Inflammation by 12-Lipoxygenases - PMC
In mice, there are seven functional LOX genes (Alox5, Alox12, Alox12b, Alox15, Alox8, Aloxe3, and Aloxe12), three or four functional genes in zebrafish ...
[39]
Identification of PpoA from Aspergillus nidulans as a Fusion Protein ...
This study aimed to characterize the biochemical properties of PpoA, a fungal DOX that is involved in the regulation of the life cycle of A. nidulans (43).<|separator|>
[40]
The opportunistic pathogen Pseudomonas aeruginosa ... - PNAS
We report that PA1169 encodes a secretable arachidonate 15-lipoxygenase (LoxA), an enzyme activity generally believed to be absent from bacteria.
[41]
A chloroplast lipoxygenase is required for wound-induced jasmonic ...
Sep 12, 1995 · Plant lipoxygenases are thought to be involved in the biosynthesis of lipid-derived signaling molecules. The potential involvement of a ...
[42]
The 13-lipoxygenase GmLOX6 is involved in JA biosynthesis and ...
The 13-lipoxygenase GmLOX6 is involved in JA biosynthesis and serves as a positive regulator of salt stress tolerance in soybean ... Plant J. 2025 Nov;124(3): ...
[43]
The lipoxygenase gene OsRCI-1 is involved in the biosynthesis of ...
May 10, 2022 · The lipoxygenase gene OsRCI-1 is involved in the biosynthesis of herbivore-induced JAs and regulates plant defense and growth in rice. Plant ...
[44]
A dual positional specific lipoxygenase functions in the generation of ...
Feb 25, 2015 · Plant LOX are classified according to the position of oxygenation in the carbon backbone of LA. This occurs either at carbon atom 9 (9-LOX) ...
[45]
Recombinant Lipoxygenases and Hydroperoxide Lyases for the ...
Dec 11, 2019 · Green leaf volatiles (GLVs) are mainly C6- and in rare cases also C9-aldehydes, -alcohols, and -esters, which are released by plants in ...
[46]
OsLOX2, a rice type I lipoxygenase, confers opposite effects on seed ...
May 4, 2014 · Some members of the lipoxygenase (LOX) family function in degradation of storage lipids during the seed germination, but little is known about ...
[47]
Lipoxygenases during Brassica napus seed germination - PubMed
These results suggest that 13-lipoxygenases acting on free fatty acids dominate during B. napus seed germination.
[48]
Arabidopsis lox3 lox4 double mutants are male sterile and defective ...
Fertility and flower development are both controlled in part by jasmonates, fatty acid-derived mediators produced via the activity of 13-lipoxygenases ...
[49]
New insights into the early steps of oil body mobilization during ...
It can be concluded that storage lipids are sufficient for proper olive pollen germination. A lipase and a lipoxygenase are likely involved in oil body ...Missing: seed maturation
[50]
A 13-lipoxygenase, TomloxC, is essential for synthesis of C5 flavour ...
Jan 22, 2014 · The lipoxygenase pathway is well known for generating C6 volatiles that are abundant in tomato fruits, most notably (Z)-3-hexenal, hexenol, ...
[51]
The Pepper Lipoxygenase CaLOX1 Plays a Role in Osmotic ...
In plants, lipoxygenases (LOXs) are involved in various physiological processes, including defense responses to biotic and abiotic stresses.
[52]
CmLOX10 positively regulates drought tolerance through jasmonic ...
Oct 15, 2020 · Drought stress severely impairs plant growth and production. Lipoxygenase (LOX), a master regulator for lipid peroxidation, is critical for ...<|control11|><|separator|>
[53]
Arabidopsis Transcriptomics Reveals the Role of Lipoxygenase2 ...
May 28, 2024 · This leads to defense responses with LOX2 playing an important role in plant resistance against caterpillar herb-ivory.
[54]
Leukotriene biosynthetic enzymes as therapeutic targets - PMC
The central enzyme in cellular leukotriene biosynthesis, 5-lipoxygenase (5-LOX), requires a set of stimulatory factors for full activity and is supported by two ...
[55]
Biosynthesis of leukotriene B4 - ScienceDirect.com
Leukotriene B4 (LTB4) is a lipid mediator derived from arachidonic acid (AA) by the sequential action of 5-lipoxygenase (5-LOX), 5-lipoxygenase-activating ...
[56]
Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis - PubMed
Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and pro-resolution.
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Novel Lipid Mediators Promote Resolution of Acute Inflammation
Nov 12, 2010 · Through transcellular biosynthesis, 15R-HETE is further converted to 15-epi-LXA4 by 5-LOX. As noted, both EPA and DHA are substrates for ...
[58]
Role of 12-hLO In Platelet Hemostasis and Thrombosis | Blood
Nov 19, 2010 · Platelet 12-Lipoxygenase Is Required for Dense Granule Secretion and Platelet Aggregation: Role of 12-hLO In Platelet Hemostasis and Thrombosis ...
[59]
12-Lipoxygenase: A Potential Target for Novel Anti-Platelet ...
12-LOX may be a viable future target for anti-platelet therapy. Studies have shown that a link exists between the levels of 12-LOX and cardiovascular risks.Platelet Therapy In... · Overview Of 12-Lox · 12-Lox Inhibitors
[60]
12R-lipoxygenase deficiency disrupts epidermal barrier function
Apr 9, 2007 · We show that 12R-LOX deficiency in mice results in a severe impairment of skin barrier function. Loss of barrier function occurs without alterations in ...
[61]
Aloxe3 Knockout Mice Reveal a Function of Epidermal ...
Loss-of-function mutations in the lipoxygenase (LOX) genes ALOX12B and ALOXE3 are the second most common cause of autosomal recessive congenital ichthyosis.Missing: ALOX15B | Show results with:ALOX15B
[62]
Arachidonate 15-lipoxygenase type B: Regulation, function, and its ...
Indeed, ALOX12B and ALOXE3 have been shown to be crucial to corneocyte lipid envelope through incorporation of ω-hydroxy-ceramides (Zheng et al., 2011). In ...<|separator|>
[63]
Male Subfertility Induced by Heterozygous Expression of ...
Taken together these data suggest that systemic inactivation of the Alox15 gene normalizes the reduced fertility of male Sec46Ala-Gpx4+/− mice by improving the ...Missing: knockout | Show results with:knockout
[64]
Oxidative Stress in the Male Germline: A Review of Novel Strategies ...
Additionally, the production of an ALOX15 knockout mouse model has shown that the loss of this enzyme does not compromise sperm production per se. However ...
[65]
Deficiency in platelet 12-lipoxygenase exacerbates inflammation ...
Mar 18, 2025 · We found that mice deficient in platelets' 12-lipoxygenase (12-LOX) demonstrate exacerbated inflammation and worse outcomes following severe acute respiratory ...
[66]
Leukotriene B4, an endogenous stimulator of the innate immune ...
This mediator was initially recognized for its involvement in the recruitment of neutrophils. However, in the last decade, LTB4 has been clearly demonstrated to ...
[67]
A critical role of leukotriene B4 in neutrophil migration to infectious ...
Our results suggest that LTB4, but not prostaglandins or PAF, is an important chemoattractant involved in neutrophil recruitment to infection sites in SL-CLP.
[68]
Pathophysiology of the cysteinyl leukotrienes and effects ... - PubMed
Asthmatic patients demonstrate increased production of cysteinyl leukotrienes during naturally occurring asthma and acute asthma attacks as well as after ...
[69]
Cysteinyl Leukotrienes in Allergic Inflammation - PubMed - NIH
While CysLT-mediated functions in the effector phase of allergic inflammation and asthma have been established for some time, recent work has demonstrated novel ...
[70]
Resolvins in Inflammation: Pro-resolving Mediators
Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent ...
[71]
15-Lipoxygenase promotes resolution of inflammation in ... - Nature
Jan 4, 2024 · These results provide evidence that lymphatic 15-LO may represent a therapeutic target for LD by serving as a mediator of T reg cell populations to resolve ...
[72]
Inhibition of LOX by flavonoids: a structure–activity relationship study
5-LOX is expressed in leukocytes, neutrophils, eosinophils, basophils and monocytes/macrophages [3]. In resting cells, 5-LOX is located either in the cytosol, ...
[73]
Regulation and Functions of 15-Lipoxygenases in Human ...
Jul 4, 2019 · ALOX15 functions to generate specific phospholipid (PL) oxidation products crucial for orchestrating the nonimmunogenic removal of apoptotic cells (ACs).
[74]
Antiviral activity of lipoxygenase against severe fever with ... - PubMed
Antiviral activity of lipoxygenase against severe fever with thrombocytopenia syndrome virus. Protein Cell. 2025 Feb 1;16(2):143-147. doi: 10.1093/procel/ ...Missing: lipid peroxidation
[75]
Requirement of a 5-lipoxygenase-activating protein for leukotriene ...
Jan 18, 1990 · We also demonstrate that the expression of both the MK-886-binding protein and 5-lipoxygenase is necessary for leukotriene synthesis in intact cells.
[76]
5-lipoxygenase-activating protein inhibitors for inflammatory diseases
FLAP is an integral membrane protein essential for 5-LO, which is the first step in leukotriene synthesis. FLAP is linked to risk for myocardial infarction, ...
[77]
The role of lipoxygenases in pathophysiology - ScienceDirect.com
For example, 20:5 is a primary substrate for conventional LOX enzymes such as 15-LOX, 12-LOX, and 5-LOX. In addition, 18-hydroperoxy-5,8,11,14,16 ...
[78]
Functional and pathological roles of the 12- and 15-lipoxygenases
### Extracted Abstract
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Lipoxygenases in chronic liver diseases: current insights and future perspectives
### Abstract
[80]
The biological role of arachidonic acid 12-lipoxygenase (ALOX12) in ...
ALOX12 protein plays an important role in inflammation and oxidation, while abnormal DNA methylation and genetic variants of ALOX12 are associated with various ...Review · 2.4. Alox12 And Oxidative... · 3. Alox12 Related Diseases
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Inflammation Drives Alzheimer's Disease: Emphasis on 5 ... - PubMed
This review intends to highlight the role of inflammatory responses in the context of AD with the emphasis on biochemical pathways of lipid metabolism enzyme, 5 ...
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5-Lipoxygenase as an emerging target against age-related brain disorders
### Summary of 5-LOX in Age-Related Brain Pathologies
[83]
Lipoxygenase interactions with natural flavonoid, quercetin, reveal a ...
Quercetin belongs to the group of natural catecholic compounds and is known as a potent, competitive inhibitor of LOX.Missing: Artemisia 2024
[84]
Pro-inflammatory enzyme inhibition of lipoxygenases by flavonoid ...
Apr 15, 2024 · Artemisa vulgaris, is a herbal plant that is known for flavonoids, potentially inhibiting lipid peroxidation and scavenging radicals. The ...Missing: quercetin | Show results with:quercetin
[85]
Bioactive Peptides and Protein Hydrolysates as Lipoxygenase ... - NIH
Recent findings indicate that protein hydrolysates and peptides derived from both edible and non-edible bioresources can act as lipoxygenase inhibitors.
[86]
Inhibition of lipoxygenase by soy isoflavones - PubMed
May 15, 2007 · Soy isoflavones act as antioxidants due to their ability to scavenge free radicals. Isoflavones inhibit the activity of soy lipoxygenase-1 and 5 ...Missing: preservation | Show results with:preservation
[87]
Inhibitors of Human 5-Lipoxygenase Potently Interfere With ...
Jan 21, 2022 · These inhibitors suppress the activity of 5-LO through a number of different modes of action. Iron-ligand inhibitors including zileuton and ...Missing: blockers IC50
[88]
Baicalein is a potent in vitro inhibitor against both reticulocyte 15 ...
... baicalein had an IC50 of 0.64 ± 0.11 μM against 12-hLO and 1.6 ± 0.24 ... 12/15-lipoxygenase (12/15-LOX) is an enzyme, which oxidizes polyunsaturated ...Missing: IC50 | Show results with:IC50
[89]
Zileuton sodium - 5-Lipoxygenase Inhibitor - APExBIO
Free 365-day returnsZileuton sodium is an inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes(LTB4, LTC4, LTD4 and LTE4) formation with an IC50 value of 0.5μM [1]. Zileuton ...
[90]
Systematic analysis of rat 12/15-lipoxygenase enzymes reveals ...
The nonselective LOX inhibitor NDGA, as well as inhibitors of 5-LOX (AA-861), platelet-type 12-LOX (baicalein and CDC) and leukocyte-type 12/15-LOX (PD-146176) ...
[91]
Identification of Novel Human 15-Lipoxygenase-2 (h15-LOX-2 ...
h15-LOX-2 is implicated in the biosynthesis of inflammatory lipid mediators and plays a role in the development of atherosclerotic plaques, but it is still ...
[92]
The 5‐lipoxygenase inhibitor, zileuton, suppresses prostaglandin ...
Sep 3, 2010 · Zileuton is currently approved by the FDA for the prophylaxis and chronic treatment of asthma in adults and children older than 12 years.
[93]
A double-blind, vehicle-controlled study evaluating masoprocol ...
Of the 113 patients who applied topical masoprocol twice a day for 14 to 28 days, there was a mean decrease in actinic keratoses from 15.0 to 5.4 and a median ...Missing: LOX | Show results with:LOX
[94]
12-Lipoxygenase (12-LOX) Plays a Key Role in Hyperinflammatory ...
Aug 28, 2025 · These findings identify 12-LOX as a critical mediator of the hyperinflammatory response in severe COVID-19 and support its inhibition as a ...Missing: syndromes | Show results with:syndromes
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Improved catalytic performance and molecular insight for ... - Frontiers
Lipoxygenase (LOX) functions as a non-heme iron oxidoreductase, facilitating the catalysis of polyunsaturated fatty acids (PUFAs) containing 1-cis, 4-cis- ...
[96]
Lipoxygenase Inhibitor - an overview | ScienceDirect Topics
Because there are six different lipoxygenase isoforms in humans, a major challenge in the field of lipoxygenase inhibition is isoform specificity. This has been ...
[97]
Dual synergistic inhibition of COX and LOX by potential chemicals ...
May 27, 2023 · Developing new and selective COX inhibitors requires knowledge of COX structure and isoform specificity. COX's active site comprises a ...
[98]
Antiviral activity of lipoxygenase against severe fever with ...
Oct 29, 2024 · In summary, we have demonstrated that LOX exerts a virucidal effect against SFTSV, through the peroxidation of the viral lipid envelope. As a ...
[99]
Research progress on the role of lipoxygenase and its inhibitors in ...
Nov 13, 2024 · 15-LOX-2 has an inhibitory effect on prostate cancer. LOX inhibitors may effectively reduce the metabolic activity of LOX enzymes. Publication ...Missing: trials | Show results with:trials