Lipoxins
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Lipoxins
A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively. History LXA4 and LXB4 were first described by Serhan, Hamberg, and the Nobel laurate Samuelsson in 1984. They reported that human blood neutrophils, when stimulated, make these two lipoxins and that neutrophils, when stimulated by either of the LXs, mounted superoxide anion (O2−) generation and degranulation responses. Both responses are considered to be pro-inflammatory in that, w ...
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Lipoxin A4
A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively. History LXA4 and LXB4 were first described by Serhan, Hamberg, and the Nobel laurate Samuelsson in 1984. They reported that human blood neutrophils, when stimulated, make these two lipoxins and that neutrophils, when stimulated by either of the LXs, mounted superoxide anion (O2−) generation and degranulation responses. Both responses are considered to be pro-inflammatory in that, while ...
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Epi-lipoxins
Epi-lipoxins are trihydroxy (i.e. containing 3 hydroxyl residues) metabolites of arachidonic acid. They are 15''R''-epimers of their lipoxin counterparts; that is, the epi-lipoxins, 15-epi-lipoxin A4 (15-epi-LxA4) and 15-epi-lipoxin B4 (15-epi-LXB4), differ from their respective lipoxin A4 (LxA4) and lipoxin B4 (LxB4) epimers in that their 15-hydroxy residue has ''R'' rather than ''S'' chirality. Formulae for these lipoxins (Lx) are: *LxA4: 5''S'',6''R'',15''S''-trihydroxy-7''E'',9''E'',11''Z'',13''E''-ETE *LxB4: 5''S'',14''R'',15''S''-trihydroxy-6''E'',8''Z'',10''E'',12''E''-ETE *15-epi-LxA4: 5''S'',6''R'',15''R''-trihydroxy-7''E'',9''E'',11''Z'',13''E''-eicosatetraenoic acid *15-epi-LxB4: 5''S'',14''R'',15''R''-trihydroxy-6''E'',8''Z'',10''E'',12''E''-eicosatrienoic acid The two-epi-Lx's as well as the two lx's are nonclassic eicosanoids that, like other members of the specialized pro-resolving mediators class of autocoids, form during and act to resolve inflammatory r ...
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Specialized Pro-resolving Mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins. SPM join the long list of other physiological agents which tend to limit inflammation (see ) including glucocorticoids, interleukin 10 (an anti-inflammatory cytokine), interleukin 1 receptor antagonist (an inhibitor of the action of pro-inflammatory cytokine, interleukin 1), annexin A1 (an inhibitor of formation of pro-inflammatory metabolites of polyunsaturated fatty acids), and the gaseous resolvins, carbon monoxide (see ), nitric oxide (see ), and hydrogen sulfide (see and ). T ...
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Cyclooxygenase 2
Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene. In humans it is one of two cyclooxygenases. It is involved in the conversion of arachidonic acid to prostaglandin H2, an important precursor of prostacyclin, which is expressed in inflammation. Function PTGS2 (COX-2), converts arachidonic acid (AA) to prostaglandin endoperoxide H2. PTGSs are targets for NSAIDs and PTGS2 (COX-2) specific inhibitors called coxibs. PTGS-2 is a sequence homodimer. Each monomer of the enzyme has a peroxidase and a PTGS (COX) active site. The PTGS (COX) enzymes catalyze the conversion of arachidonic acid to prostaglandins in two steps. First, hydrogen is abstracted from carbon 13 of arachidonic acid, and then two molecules of oxygen are added by the PTGS2 (COX-2), giving PGG2. Second, PGG2 is reduced ...
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ALOX15
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function Kelavkar and Badr (1999) stated that the ALOX15 gene product is implicated in antiinflammation, membrane remodeling, and cancer development/metastasis. Kelavkar and Badr (1999) described experiments yielding data that supported the hypothesis that loss of the TP53 gene, or gain-of-function activities resulting from the expression of its mutant forms, regulates ALOX15 promoter activity in human and in mouse, albeit in directionally opposite manners. These studies defined a direct link between ALOX15 gene activity and an established tumor-suppressor gene located in close chromosomal proximity. Kelavkar and Badr (1999) referred to this as evidence that 15-lipoxygenase is a mutator gene. ▼ Mapping By PCR anal ...
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15-lipoxygenase
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function Kelavkar and Badr (1999) stated that the ALOX15 gene product is implicated in antiinflammation, membrane remodeling, and cancer development/metastasis. Kelavkar and Badr (1999) described experiments yielding data that supported the hypothesis that loss of the TP53 gene, or gain-of-function activities resulting from the expression of its mutant forms, regulates ALOX15 promoter activity in human and in mouse, albeit in directionally opposite manners. These studies defined a direct link between ALOX15 gene activity and an established tumor-suppressor gene located in close chromosomal proximity. Kelavkar and Badr (1999) referred to this as evidence that 15-lipoxygenase is a mutator gene. ▼ Mapping By PCR anal ...
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ALOX12
ALOX12 (), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12''S''-Lipoxygenase, 12-LOX, and 12''S''-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ''ALOX12'' gene which is located along with other lipoyxgenases on chromosome 17p13.3. ALOX12 is 75 kilodalton protein composed of 663 amino acids. Nomenclature Other systematic names for ALOX12 include 12S-Lipoxygenase, platelet-type 12-lipoxygenase, arachidonate:oxygen 12-oxidoreductase, Delta12-lipoxygenase, 12Delta-lipoxygenase, and C-12 lipoxygenase. ALOX12, often termed plate platelet-type 12-lipoxygenase, is distinguished from leukocyte-type 12-lipoxygenase which is found in mice, rats, cows, and pigs but not humans. Leukocyte-type 12-lipoxygenase in these animal species shares 73-86% amino acid identity with human ALOX15 but only 57-66% identity with human platelet-type 12-lipoxygenase and, like ALOX15, metabolizes arachidonic acid primarily to 15(''S'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13' ...
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Lipoxygenase
Lipoxygenases () are a family of (non-heme) iron-containing enzymes most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as autocrine signals that regulate the function of their parent cells, paracrine signals that regulate the function of nearby cells, and endocrine signals that regulate the function of distant cells. The lipoxygenases are related to each other based upon their similar genetic structure and dioxygenation activity. However, one lipoxygenase, ALOXE3, while having a lipoxygenase genetic structure, possesses relatively little dioxygenation activity; rather its primary activity appears to be as an isomerase that catalyzes the conversion of hydroperoxy unsaturated fatty acids to their 1,5-epoxide, hydroxyl derivatives. Lipoxygenases are found in eukaryotes (plants, fungi, animals, protists); while the third domain of terrestrial life, the archaea, pos ...
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5-lipoxygenase
Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms essential fatty acids (EFA) substrates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases. Gene The ''ALOX5'' gene, which occupies 71.9 kilobase pairs (kb) on chromosome 10 (all other human lipoxygenases are clustered together on chromosome 17), is composed of 14 exons divided by 13 introns encoding the mature 78 kilodalton (kD) ALOX5 protein consisting of 673 amino acids. The gene promoter region of ALOX5 contains 8 GC boxes but lacks TATA boxes or CAT boxes and thus resembles the gene promoters of typical housekeeping genes. Five of the 8 GC boxes are arranged in tandem and are recognized by t ...
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Arachidonic Acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachis'' (peanut), but peanut oil does not contain any arachidonic acid. Chemistry In chemical structure, arachidonic acid is a carboxylic acid with a 20-carbon chain and four ''cis''-double bonds; the first double bond is located at the sixth carbon from the omega end. Some chemistry sources define 'arachidonic acid' to designate any of the eicosatetraenoic acids. However, almost all writings in biology, medicine, and nutrition limit the term to ''all cis''-5,8,11,14-eicosatetraenoic acid. Biology Arachidonic acid is a polyunsaturated fatty acid present in the phospholipids (especially phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositides) of membranes of the body's cells, and is abundant in the brain, muscles, an ...
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Maresin
Maresin 1 (MaR1 or 7''R'',14''S''-dihydroxy-4''Z'',8''E'',10''E'',12''Z'',16''Z'',19''Z''-docosahexaenoic acid) is a macrophage-derived mediator of inflammation resolution coined from macrophage mediator in resolving inflammation. Maresin 1, and more recently defined maresins, are 12-lipoxygenase-derived metabolites of the omega-3 fatty acid, docosahexaenoic acid (DHA), that possess potent anti-inflammatory, pro-resolving, protective, and pro-healing properties similar to a variety of other members of the specialized proresolving mediators (SPM) class of polyunsaturated fatty acid (PUFA) metabolites. SPM are dihydroxy, trihydroxy, and epoxy-hydroxy metabolites of long chain PUFA made by certain dioxygenase enzymes viz., cyclooxygenases and lipoxygenases. In addition to the maresins, this class of mediators includes: the 15-lipoxygenase (i.e. ALOX15 and/or possibly ALOX15B)-derived Lipoxin A4 and B4 metabolites of the omega 6 fatty acid, arachidonic acid; the cyclooxygenase 2- ...
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Inflammatory Response
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', ''dolor'', ''rubor'', ''tumor'', and ''functio laesa''). Inflammation is a generic response, and therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. In contrast, too much inflammation, in the ...
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