ALOX12 (), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12''S''-Lipoxygenase, 12-LOX, and 12''S''-LOX is a

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 auto ...

-type

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that in humans is encoded by the ''ALOX12''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

which is located along with other lipoyxgenases on chromosome 17p13.3. ALOX12 is 75

kilodalton The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at ...

protein composed of 663 amino acids.

Nomenclature

Other

systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature. A semisystematic name or semitrivial ...

s 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 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 importa ...

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''E''-eicosatetraenoic acid (i.e. 15(''S'')-HpETE; see 15-Hydroxyeicosatetraenoic acid). Accordingly, rodent leukocyte 12-lipoxygenase is deemed an

ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

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 In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are fa ...

to membrane

phospholipids Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

; 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

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 A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...

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

). ALOX12 is also distinguished from arachidonate 12-lipoxygenase, 12R type (ALOX12B), which metabolizes arachidonic acid to the ''R''

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

of 12(''S'')-HpETE viz., 12(''R'')-hydroperoxy-5''Z'',8''Z'',10''E'',14''Z''-icosatetraenoic acid (12(''R'')-HpETE), a product with very different pathophysiological roles than that of 12(''S'')-HpETE (see

ALOX12B Arachidonate 12-lipoxygenase, 12R type, also known as ALOX12B, 12''R''-LOX, and arachidonate lipoxygenase 3, is a lipoxygenase-type enzyme composed of 701 amino acids and encoded by the ''ALOX12B'' gene. The gene is located on chromosome 17 at po ...

Discovery

ALOX12, originally called arachidonate 12-lipoxygenase, was first characterized by the Nobel Laureate,

Bengt I. Samuelsson Bengt Ingemar Samuelsson (born 21 May 1934) is a Swedish biochemist. He shared with Sune K. Bergström and John R. Vane the 1982 Nobel Prize for Physiology or Medicine for discoveries concerning prostaglandins and related substances. Education a ...

, and his famed colleague, Mats Hamberg, in 1974 by showing that human

platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

metabolize

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 ''arachi ...

not only by the well-known

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prosta ...

pathway into

prostaglandin The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...

s 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. In 1975, the first biological activity was attached to this metabolite in studies showing that it simulated the

chemotaxis Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...

of human

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

s. During the several years thereafter, human ALOX12 was purified, characterized biochemically, and had its gene molecularly

cloned Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, c ...

Tissue distribution

Based predominantly on the presence of its

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

, human ALOX12 is distributed predominantly in blood platelets and

leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

s and at lower levels in the basal layer of the epidermis (particularly in the skin lesions of

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

islets of Langerhans The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...

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 Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...

(PUFA) substrates which are released from storage in membrane

phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

s by cell stimulation. The enzyme participates in

arachidonic acid metabolism 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 ''arach ...

by conducting the following

chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...

wherein its substrates are

(also termed as arachidonate or, chemically, as 5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid) and O₂ (i.e.

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...

) and its

product Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...

is 12''S''-hydroperoxy-5''Z'',8''Z'',10''E'',14''Z''-eicosatetraenoic acid (i.e. 12''S''-hydroperoxyeicosatetraenoic acid or 12''S''-HpETE): * arachidonate + O₂ → 12''S''-hydroperoxy-5''Z'',8''Z'',10''E'',14''Z''-eicosatetraenoic acid In cells, 12''S''HpETE may be further metabolized by ALOX12 itself, by

ALOXE3 Epidermis-type lipoxygenase 3 (ALOXE3 or eLOX3) is a member of the lipoxygenase family of enzymes; in humans, it is encoded by the ''ALOXE3'' gene. This gene is located on chromosome 17 at position 13.1 where it forms a cluster with two other lipo ...

or possibly other, as yet not fully identified, hepoxilin synthases to

hepoxilin Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid ...

A3 (8''R/S''-hydroxy-11,12-oxido-5''Z'',9''E'',14''Z''-eicosatrienoic acid) and B3 (10''R/S''-hydroxy-11,12-oxido-5''Z'',8''Z'',14''Z''-eicosatrienoic acid): * 12''S''-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid → 8''R/S''-hydroxy-11,12-oxido-5''Z'',9''E'',14''Z''-eicosatrienoic acid + 10''R/S''-hydroxy-11,12-oxido-5''Z'',8''Z'',14''Z''-eicosatrienoic acid Hepoxilins can promote certain

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

responses, increase pain perception (i.e. tactile

allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...

), regulate regional blood flow, and contribute to the regulation of blood pressure in animal models (see

Hepoxilins Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoi ...

). Far more commonly, however, 12''S''-HpETE is rapidly reduced to its

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

product by ubiquitous cellular peroxidase activities thereby forming 12''S''-hydroxy-5''Z'',8''Z'',10''E'',14''Z''-eicosatetraenoic acid, i.e. 12-hydroxyeicosatetraenoic acid or 12''S''-HETE: * 12''S''-hydroperoxy-5(''Z''),8(''Z''),10(''E''),14(''Z'')-eicosatetraenoic acid → 12''S''-hydroxy-5(''Z''),8(''Z''),10(''E''),14(''Z'')-eicosatetraenoic acid 12''S''-HETE promotes inflammation responses, may be involved in the perception of

puritis Itch (also known as pruritus) is a Wikt:sensation, sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of Sensory system, sensory experience. Itch has many similarities to pain, ...

(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 Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...

docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lino ...

(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) which metabolized to 7''R'',14''S''-dihydroxy-4''Z'',8''E'',10''E'',12''Z'',16''Z'',19''Z''-docosahexaenoic acid (i.e.

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, an ...

1), by an unidentified

epoxide hydrolase Epoxide hydrolases (EH's), also known as epoxide hydratases, are enzymes that metabolize compounds that contain an epoxide residue; they convert this residue to two hydroxyl residues through an epoxide hydrolysis reaction to form diol products. ...

-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 Leukotriene A4 (LTA4) is a leukotriene, and is the precursor for the productions of LTB4 (leukotriene B)) and LTC4 (leukotriene C4). Biosynthesis of Leukotriene A4 Following the biosynthesis of eicosanoid, triggered as a result of infection or ...

(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 (5''S'',6''R'',15''S''-trihydroxy-7''E'',9''E'',11''Z'',13''Z''-eicosatetraenoic acid) and lipoxin B4 (5''S'',14''R'',15''S''-trihydroxy-6''E'',8''Z'',10''E'',12''E''-eicosatetraenoic acid); both lipoxins are SPMs with many SPM-like activities (see

lipoxin 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-resolvin ...

). ALOX12 may also metabolize lesser amounts of DHA to secondary products including 17-hydroperoxy-DHA, 11-hydroperoxy-DHA, and 8,14-dihydroxy-DHA ALOX12 may likewise metabolize 5(''S'')-HETE to 5''S'',12''S''-dihydroxyeicosatetraenoic acid (12,15-diHETE) and 15''S''-HETE to 14,15''S''-diETE. While these compounds have not been thoroughly evaluated for bioactivity, 17-hydroperoxy-HDHA and the reduced product to which it is rapidly converted in cells, 17-hydroxy-HDHA, have been shown to inhibit the growth of cultured human prostate cancer cell by causing them to enter

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

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 Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

adipose Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

cell/tissue dysfunction, and obesity; b) the development of

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...

and

Steatohepatitis Steatohepatitis is a type of fatty liver disease, characterized by inflammation of the liver with concurrent fat accumulation in liver. Mere deposition of fat in the liver is termed steatosis, and together these constitute fatty liver changes. T ...

; b) regulating blood vessel contraction, dilation, pressure, remodeling, and

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

; c) maintaining normal renal, neurological, and brain function; and d) the development of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

. In these studies, it is usually unclear which, if any metabolite(s) of ''Alox12'' was implicated.

Preclinical studies

Metabolic syndrome

The

metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndrome ...

is a clustering of at least three of five of the following medical conditions: abdominal (central)

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

elevated blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high blo ...

, elevated fasting plasma glucose (or overt

), high serum triglycerides, and low

high-density lipoprotein High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are ty ...

(HDL) levels. ALOX12 and its metabolite, 12(''S'')-HETE, are elevated in the

of patients with

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

as well as in the fat cells of

white adipose tissue White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes. In humans, the healthy amount of white adipose ti ...

of morbidly obese type 2 diabetic patients. The

PP cell Pancreatic polypeptide cells (PP cells), or formerly as gamma cells (γ-cells), or F cells, are cells in the pancreatic islets (Islets of Langerhans) of the pancreas. Their main role is to help synthesize and regulate the release of pancreatic pol ...

s (i.e. gamma cells) of the pancreas islets appear to be the major if not only site where ALOX12 is expressed in these patients. The studies propose that in the islets of Langerhans ALOX12 and its 12(''S'')-HETE product cause excessive production of

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

and inflammation which lead to losses in

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

-secreting

beta cell Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...

s and thereby types 1 and 2 diabetes and that in adipose tissue the excess in AlOX12, 12(''S'')-HETE, reactive oxygen species, and inflammation lead to fat cell dysfunction (also see 12-HETE#Inflammation and inflammatory diseases and 12-HETE#Diabetes). Indeed, in one study a

Single-nucleotide polymorphism In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...

, rs2073438, located in an

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

region of the ''ALOX12'' gene was significantly associated with total and percentage fat mass of obese compared to non-obese young Chinese men. ALOX12 and 12(''S'')-HETE are likewise implicated in essential hypertension (see next section). Hence, ALOX12 and its metabolite(s) may contribute to the development and/or progression of obesity, diabetes, hypertension, and/or the metabolic syndrome.

Blood vessels

A selective but not totally specific inhibitor of ALOX12 reduced the growth response of cultured human

endothelial cell The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

s to

basic fibroblast growth factor Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(F ...

and

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

(VEGF); this reduction was partially reversed by 12(''S'')-HETE; 12(''S'')-HETE also stimulates human prostate cell lines to produce VEGF. These results suggest that growth responses to the two growth factors involves their stimulation of 12(''S'')-HETE production by endothelial cells and therefore that ALOX12 may be a target for reducing the neo-vascularization that promotes arthritic and cancer diseases. 12(''S'')-HETE also dilates human coronary microcirculation arteries by activating these vessels' smooth muscle BKca

Potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...

s and is therefore suggested to be an Endothelium-derived hyperpolarizing factor. Finally, a

single nucleotide variant In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

in the ''ALOX12'' gene (R261Q 957 G>A has been associated with

essential hypertension Essential hypertension (also called primary hypertension, or idiopathic hypertension) is the form of hypertension that by definition has no identifiable secondary cause. It is the most common type affecting 85% of those with high blood pressure. T ...

and elevation in the urinary excretion of 12(''S'')-HETE in humans and may be a contributing factor for to essential hypertension (see also 12-HETE#Blood pressure).

Alzheimer's disease

Patients with

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 Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator ...

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. In a single study, ALOX12 mRNA was found elevated in the brain tissue of

Alzheimer disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...

patients compared to control patients. These results suggest that ALOX12 (or ALOX15) may contribute to the development of Alzheimer's disease in humans.

Cancer

Studies in prostate cancer find that human prostate cancer cell lines in culture overexpress ALOX12, overproduce 12(''S'')-HETE, and respond to 12(''S'')-HETE by increasing their rate of proliferation, increasing their cell surface expression of

integrins Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

, increasing their survival and delaying their

, and increasing their production of

and

MMP9 Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extrace ...

(i.e. Matrix metallopeptidase 9); selective (but not entirely) specific ALOX12 inhibitors reduced the proliferation and survival of these cells (see also 12-HETE#prostate cancer). These finding suggest that ALOX12 and its 12(''S'')-HETE product may contribute to the growth and spread of prostate cancer in humans. Recently, hypermethylation of the ''ALOX12'' gene in prostate cancer tissue was associated with clinical predictors for a high rate of recurrent disease. 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). ALOX12 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with

Keratin 5 Keratin 5, also known as KRT5, K5, or CK5, is a protein that is encoded in humans by the ''KRT5'' gene. It dimerizes with keratin 14 and forms the intermediate filaments (IF) that make up the cytoskeleton of basal epithelial cells. This protein i ...

and

LMNA Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins. Function In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, res ...

as screened in a yeast two-hybrid interaction library from human epidermoid carcinoma

A431 cells A431 cells are a model human cell line (epidermoid carcinoma) used in biomedical research. Characteristics A431 cells were established from an epidermoid carcinoma in the skin (epidermis) of an 85- year-old female patient. Epidermal growth factor ...

; these proteins are candidates for regulating 12-LOX, particularly in tumor cells.

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.

Other associations

The ''ALOX12'' gene has susceptibility alleles (rs6502997, rs312462, rs6502998, and rs434473) for the

parasitic disease A parasitic disease, also known as parasitosis, is an infectious disease caused by parasites. Parasites are organisms which derive sustenance from its host while causing it harm. The study of parasites and parasitic diseases is known as parasitolog ...

, human congenital

toxoplasmosis Toxoplasmosis is a parasitic disease caused by ''Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or months ...

Fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...

bearer of these alleles thus suffer an increased susceptibility to this disease.