ALOX12

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-5Z,8Z,11Z,13E-eicosatetraenoic acid (i.e. 15(S)-HpETE; see 15-Hydroxyeicosatetraenoic acid). Accordingly, rodent leukocyte 12-lipoxygenase is deemed an ortholog of ALOX15 and is designated as Alox15. Human ALOX12 and ALOX15 along with rodent leukocyte-type Alox12 and Alox15 are commonly termed 12/15-lipoxygenases based on their ability to metabolize arachidonic acid to both 12(S)-HpETE and 15(S)-HpETE and to conduct this same metabolism on arachidonic acid that is esterified to membrane phospholipids; human ALOX15B makes 15(S)-HpETE but not 12(S)-HpETE and therefore is not regarded as a 12/15-lipoxygenase. Studies on the role of ALOX12 in pathophysiology using the main models for such functional studies, rats and mice, are complicated because neither species possesses a lipoxygenase that makes a predominance of 12(S)-HETE and therefore is metabolically equivalent to ALOX12. For example, the functions inferred for Alox12 in mice made deficient in Alox12 using knockout methods may not indicate a similar function for ALOX12 in humans due to differences in these two enzymes' metabolic activities. The function of ALOX12 is further clouded by human ALOX15 which metabolizes arachidonic acid primarily to 15(S)-HpETE but also makes lesser but still significant amounts of 12(S)-HpETE (see ALOX15). ALOX12 is also distinguished from arachidonate 12-lipoxygenase, 12R type (ALOX12B), which metabolizes arachidonic acid to the R stereoisomer of 12(S)-HpETE viz., 12(R)-hydroperoxy-5Z,8Z,10E,14Z-icosatetraenoic acid (12(R)-HpETE), a product with very different pathophysiological roles than that of 12(S)-HpETE (see ALOX12B). == Discovery ==

ALOX12, originally called arachidonate 12-lipoxygenase, was first characterized by the Nobel Laureate, Bengt I. Samuelsson, and his famed colleague, Mats Hamberg, in 1974 by showing that human platelets metabolize arachidonic acid not only by the well-known cyclooxygenase pathway into prostaglandins and 12-hydroxyheptadecatrienoic acid but also by a cyclooxygenase-independent pathway to 12(S)-hydroperoxy-5,8,10,14-eicosatetraenoic acid; this activity was the first mammalian lipoxygenase activity to be characterized. During the several years thereafter, human ALOX12 was purified, characterized biochemically, and had its gene molecularly cloned. == Tissue distribution ==

Based predominantly on the presence of its mRNA, human ALOX12 is distributed predominantly in blood platelets and leukocytes and at lower levels in the basal layer of the epidermis (particularly in the skin lesions of psoriasis), islets of Langerhans within the pancreas, and certain cancers. ==Enzyme activities==

The control of ALOX12 activity appears to rest principally on the availability of its polyunsaturated fatty acid (PUFA) substrates which are released from storage in membrane phospholipids by cell stimulation. The enzyme participates in arachidonic acid metabolism by conducting the following chemical reaction wherein its substrates are arachidonic acid (also termed as arachidonate or, chemically, as 5Z,8Z,11Z,14Z-eicosatetraenoic acid) and O2 (i.e. oxygen) and its product is 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (i.e. 12S-hydroperoxyeicosatetraenoic acid or 12S-HpETE): • arachidonate + O2 → 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid In cells, 12SHpETE may be further metabolized by ALOX12 itself, by ALOXE3 or possibly other, as yet not fully identified, hepoxilin syntheses to hepoxilin A3 (8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and B3 (10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid): • 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid → 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid + 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid Hepoxilins can promote certain inflammation responses, increase pain perception (i.e. tactile allodynia), regulate regional blood flow, and contribute to the regulation of blood pressure in animal models (see Hepoxilins). Far more commonly, however, 12S-HpETE is rapidly reduced to its hydroxyl product by ubiquitous cellular peroxidase activities thereby forming 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid, i.e. 12-hydroxyeicosatetraenoic acid or 12S-HETE: • 12S-hydroperoxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid → 12S-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid 12S-HETE promotes inflammation responses, may be involved in the perception of puritis (i.e. itching) in the skin, and regulates regional blood flow in animal models; it also promotes the malignant behavior of cultured human cancer cells as well as the growth of certain cancers in animal models (see 12-HETE). While arachidonate and 12(S)-HETE are the predominant substrates and products, respectively, of ALOX12, the enzyme also metabolizes other PUFA. It metabolizes the omega-3 fatty acid, docosahexaenoic acid (DHA i.e., 4(Z),7(Z),10(Z),13(Z),16(Z),19(Z)-docosahexaenoic acid to 14(R)-hydroperoxy-4(Z),8(Z),10(Z),12(E),16(Z),19(Z)-docosahexaenoic acid)(i.e. 17-hydroperoxy-DHA) Then, ALOX12 or an unidentified epoxidase-type enzyme may metabolize this intermediate to an epoxide, 13,14-epoxy-4(Z),7(Z),9(E),11(E),16(Z),19(Z)-docosahexaenoic acid (i.e. 13,14-e-maresin) This is further metabolized to 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (i.e. Maresin 1), by an unidentified epoxide hydrolase-type enzyme: • DHA → 17-hydroperoxy-DHA → 13,14-e-maresin → Maresin-1 Maresin 1 has a set of activities that may oppose those of 12(S)-HETE and the hepoxilins; it is a member of a class of PUFA metabolites termed Specialized pro-resolution mediators (SPMs) which possess anti-inflammatory, pain-alleviating, and other defensive activities. ALOX12 also acts on leukotriene A4 (LTA4) in a two cellular reaction termed transcellular metabolism: human neutrophils metabolize arachidonic acid to its 5,6-epoxide, LTA4, and releases this intermediate to nearby neutrophils which metabolize it to lipoxin A4 (5S,6R,15S-trihydroxy-7E,9E,11Z,13Z-eicosatetraenoic acid) and lipoxin B4 (5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid); both lipoxins are SPMs with many SPM-like activities (see lipoxin). ALOX12 may also metabolize lesser amounts of DHA to secondary products including 17-hydroperoxy-DHA, 11-hydroperoxy-DHA, and 8,14-dihydroxy-DHA == Animal studies ==

Studies on rodents lacking or made deficient in the leukocyte-type 12-lipoxygenase, Alox12 (which is most closely related to human ALOX15) implicate this enzyme in: a) preventing the development and complications of dietary-induced and/or genetically induced diabetes, adipose cell/tissue dysfunction, and obesity; b) the development of atherosclerosis and Steatohepatitis; b) regulating blood vessel contraction, dilation, pressure, remodeling, and angiogenesis; c) maintaining normal renal, neurological, and brain function; and d) the development of Alzheimer's disease. In these studies, it is usually unclear which, if any metabolite(s) of Alox12 was implicated. == Preclinical studies ==

Metabolic syndrome The metabolic syndrome is a clustering of at least three of five of the following medical conditions: abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose (or overt diabetes), high serum triglycerides, and low high-density lipoprotein (HDL) levels. ALOX12 and its metabolite, 12(S)-HETE, are elevated in the islets of Langerhans of patients with type 1 diabetes or type 2 diabetes as well as in the fat cells of white adipose tissue of morbidly obese type 2 diabetic patients. located in an intron region of the ALOX12 gene was significantly associated with total and percentage fat mass of obese compared to non-obese young Chinese men. Alzheimer's disease Patients with Alzheimer's disease or other forms of dementia have significantly higher levels of 12(S)-HETE (and 15(S)-HETE) in cerebrospinal fluid compared to aged-matched normal individuals. Complementary studies in rodent models bearing human mutated genes for Amyloid precursor protein and/or tau protein (see tau protein#Clinical significance) that produce Alzheimer's dementia-like syndromes implicate 12(S)-HETE, 15(S)-HETE, and a 12/15-lipoxygenase type enzyme in the development and progression of the Alzhiemer's disease-like symptoms and findings in these animals. Some studies have found that 12(S)-HETE also promotes the growth and/or related pro-malignant behaviors of various other types of cultured cancer cell lines (see 12-HETE#Other cancers). Platelet function Although first identified in human platelets, the role of ALOX12 and its major metabolites, 12(S)-HpETE and 12(S)-HETE in platelet function remains controversial and unclear; it is possible that the ALOX12-12(S)-HETE metabolic pathway has dual functions in promoting or inhibiting platelet responses depending on the stimulating agent and response studied but that inhibiting ALOX12 may ultimately prove useful in inhibiting platelet-related blood clotting. rs312462, rs6502998, and rs434473) for the parasitic disease, human congenital toxoplasmosis. Fetus bearer of these alleles thus suffer an increased susceptibility to this disease. == References ==