Arachidonate 12-lipoxygenase, 12R type, also known as ALOX12B, 12''R''-LOX, and arachidonate lipoxygenase 3, is a

lipoxygenase Lipoxygenases () (LOX) are a family of (non- heme) iron-containing enzymes, more specifically oxidative enzymes, most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into ce ...

-type enzyme composed of 701 amino acids and encoded by the ''ALOX12B''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. The gene is located on chromosome 17 at position 13.1 where it forms a cluster with two other lipoxygenases,

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 lip ...

and

ALOX15B Arachidonate 15-lipoxygenase type II is an enzyme that in humans is encoded by the ''ALOX15B'' gene. ALOX15B, also known as 15-lipoxygenase-2 (15-LO-2 or 15-LOX-2), is distinguished from its related oxygenase, ALOX15 or 15-lipoxygenase-1. Funct ...

. Among the human lipoxygenases, ALOX12B is most closely (54% identity) related in amino acid sequence to

Activity

ALOX12B oxygenates

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 a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...

by adding molecular oxygen (O₂) in the form of a

hydroperoxyl The hydroperoxyl radical, also known as the hydrogen superoxide, is the protonated form of superoxide with the chemical formula HO2, also written HOO•. This species plays an important role in the atmosphere and as a reactive oxygen species ...

(HO₂) residue to its 12th carbon thereby forming 12(''R'')-hydroperoxy-5''Z'',8''Z'',10''E'',14''Z''-icosatetraenoic acid (also termed 12(''R'')-HpETE or 12''R''-HpETE). When formed in cells, 12''R''-HpETE may be quickly 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 ...

analog (OH), 12(''R'')-hydroxy-5Z'',8''Z'',10''E'',14''Z''-eicosatetraenoic acid (also termed 12(''R'')-HETE or 12''R''-HETE), by ubiquitous

peroxidase Peroxidases or peroxide reductases ( EC numberbr>1.11.1.x are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides, and should not be confused with other ...

-type enzymes. These sequential metabolic reactions are: ALOX12B is also capable of metabolizing free

linoleic acid Linoleic acid (LA) is an organic compound with the formula . Both alkene groups () are ''cis''. It is a fatty acid sometimes denoted 18:2 (n−6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. Linoleic acid is a polyunsat ...

to 9(''R'')-hydroperoxy-10(E),12(Z)-octadecadienoic acid (9''R''-HpODE) which is also rapidly converted to its hydroxyl derivative, 9-Hydroxyoctadecadienoic acid (9''R''-HODE). The ''S''

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 9''R''-HODE, 9''S''-HODE, has a range of biological activities related to

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

and pain perception (see

9-Hydroxyoctadecadienoic acid 9-Hydroxyoctadecadienoic acid (or 9-HODE) has been used in the literature to designate either or both of two stereoisomer metabolites of the essential fatty acid, linoleic acid: 9(''S'')-hydroxy-10(''E''),12(''Z'')-octadecadienoic acid (9(''S' ...

. It is known or likely that 9''R''-HODE possesses at least some of these activities. For example, 9''R''-HODE, similar to 9''S''-HODE, mediates the perception of acute and chronic pain induced by heat, UV light, and inflammation in the skin of rodents (see 9-Hydroxyoctadecadienoic acid#9-HODEs as mediators of pain perception). However, production of these LA metabolites does not appear to be the primary function of ALOX12B; ALOX12B's primary function appears to be to metabolize linoleic acid that is not free but rather esterified to certain

Proposed principal activity of ALOX12B

ALOX12B targets

Linoleic acid Linoleic acid (LA) is an organic compound with the formula . Both alkene groups () are ''cis''. It is a fatty acid sometimes denoted 18:2 (n−6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. Linoleic acid is a polyunsat ...

(LA). LA is the most abundant fatty acid in the skin

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and Subcutaneous tissue, hypodermis. The epidermal layer provides a barrier to infection from environmental pathogens and regulates the ...

, being present mainly

esterified In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distinct ...

to the omega-

residue of

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...

-linked omega-hydroxylated

very long chain fatty acid A very-long-chain fatty acid (VLCFA) is a fatty acid with 22 or more carbons. Their biosynthesis occurs in the endoplasmic reticulum. VLCFA's can represent up to a few percent of the total fatty acid content of a cell. Unlike most fatty acids, V ...

s (VLCFAs) in a unique class of

ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid joined by an amide bond. Ceramides are found in high concentrations within the cell membrane of Eukaryote, eukaryotic cells, since they are co ...

s termed esterified omega-hydroxyacyl-

sphingosine Sphingosine (2-amino-4-trans-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phosphol ...

(EOS). EOS is an intermediate component in a proposed multi-step metabolic pathway which delivers VLCFAs to the cornified lipid envelop in the skin's

Stratum corneum The stratum corneum (Latin language, Latin for 'horny layer') is the outermost layer of the epidermis (skin), epidermis. Consisting of dead tissue, it protects underlying tissue from infection, dehydration, chemicals and mechanical stress. It is ...

; the presence of these

wax Waxes are a diverse class of organic compounds that are lipophilic, malleable solids near ambient temperatures. They include higher alkanes and lipids, typically with melting points above about 40 °C (104 °F), melting to give lo ...

-like, hydrophobic VLCFAs is needed to maintain the skin's integrity and functionality as a water barrier (see Lung microbiome#Role of the epithelial barrier). ALOX12B metabolizes the LA in EOS to its 9-hydroperoxy derivative; ALOXE3 then converts this derivative to three products: a) 9''R'',10''R''-trans-

epoxide In organic chemistry, an epoxide is a cyclic ether, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ...

,13''R''-hydroxy-10''E''-octadecenoic acid, b) 9-keto-10''E'',12''Z''-octadecadienoic acid, and c) 9''R'',10''R''-trans-epoxy-13-keto-11''E''-octadecenoic acid. These ALOX12B-oxidized products signal for the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

(i.e. removal) of the oxidized products from EOS; this allows the multi-step metabolic pathway to proceed in delivering the VLCFAs to the cornified lipid envelop in the skin's Stratum corneum.

Tissue distribution

ALOX12B protein has been detected in humans that in the same tissues the express ALOXE3 and ALOX15B viz., upper layers of the human skin and tongue and in tonsils. mRNA for it has been detected in additional tissues such as the lung, testis, adrenal gland, ovary, prostate, and skin with lower abundance levels detected in salivary and thyroid glands, pancreas, brain, and plasma blood leukocytes.

Clinical significance

Congenital ichthyosiform erythrodema

Deletions of ''Alox12b'' or ''AloxE2'' genes in mice cause a congenital scaly skin disease which is characterized by a greatly reduced skin water barrier function and is similar in other ways to the

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

nonbullous

Congenital ichthyosiform erythroderma A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth ...

(ARCI) disease of humans. Mutations in many of the genes that encode proteins, including ALOX12B and ALOXE3, which conduct the steps that bring and then bind VLCFA to the stratums corneum are associated with ARCI. ARCI refers to nonsyndromic (i.e. not associated with other signs or symptoms)

congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...

Ichthyosis Ichthyosis is a family of genetic disorder, genetic skin disorders characterized by Xeroderma, dry, Scleroderma, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, underlying genetic cau ...

including

Harlequin-type ichthyosis Harlequin-type ichthyosis is a genetic disorder that results in thickened skin over nearly the entire body at birth. The skin forms large, diamond/trapezoid/rectangle-shaped plates that are separated by deep cracks. These affect the shape of th ...

Lamellar ichthyosis Lamellar ichthyosis, also known as ichthyosis lamellaris and nonbullous congenital ichthyosis, is a rare inherited skin disorder, affecting around 1 in 600,000 people. Presentation Affected babies are born in a collodion membrane – a shiny, wa ...

, and

. ARCI has an incidence of about 1/200,000 in European and North American populations; 40 different mutations in ''ALOX12B'' and 13 different mutations in ''ALOXE3'' genes account for a total of about 10% of ARCI case; these mutations uniformly cause a total loss of ALOX12B or ALOXE3 function (see

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...

Proliferative skin diseases

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

and other proliferative skin diseases such as the

erythroderma Erythroderma is an inflammatory skin disease with erythema, redness and scaling that affects nearly the entire cutaneous surface.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. p. 436. . This te ...

s underlying lung cancer,

cutaneous T cell lymphoma Cutaneous T-cell lymphoma (CTCL) is a class of non-Hodgkin lymphoma, which is a type of cancer of the immune system. Unlike most non-Hodgkin lymphomas (which are generally B-cell-related), CTCL is caused by a mutation of T cells. The cancerous ...

, and drug reactions, and in

discoid lupus Discoid lupus erythematosus is the most common type of chronic cutaneous lupus (CCLE), an autoimmune skin condition on the lupus erythematosus spectrum of illnesses. It presents with red, painful, inflamed and coin-shaped patches of skin with a sc ...

seborrheic dermatitis Seborrhoeic dermatitis (also spelled seborrheic dermatitis in American English) is a long-term skin disorder. Symptoms include flaky, scaly, greasy, and occasionally itchy and inflamed skin. Areas of the skin rich in sebum, oil-producing gland ...

, subacute

cutaneous lupus erythematosus Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different d ...

, and

pemphigus foliaceus Pemphigus foliaceus is an autoimmune blistering disease of the skin. Pemphigus foliaceus causes a characteristic inflammatory attack at the subcorneal layer of epidermis, which results in skin lesions that are scaly or crusted erosions with an ...

, cutaneous levels of ALOX12B

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 ...

and 12''R''-HETE are greatly increased. It is not clear if these increases contribute to the disease by, for example, 12''R''-HETE induction of inflammation, or are primarily a consequence of skin proliferation.

Embryogenesis

The expression of Alox12b and Aloxe3

in mice parallels, and is proposed to be instrumental for, skin development in mice

embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...

; the human

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 speci ...

s of these genes, i.e. ALOX12B and ALOXE3, may have a similar role in humans.

Essential fatty acid deficiency

Severe dietary deficiency of polyunsaturated

omega 6 fatty acid Omega−6 fatty acids (also referred to as ω−6 fatty acids or ''n''−6 fatty acids) are a family of polyunsaturated fatty acids (PUFA) that share a final carbon-carbon double bond in the ''n''−6 position, that is, the sixth bond, counti ...

s leads to the essential fatty acid deficiency syndrome that is characterized by scaly skin and excessive water loss; in humans and animal models the syndrome is fully reversed by dietary omega 6 fatty acids, particularly linoleic acid. It is proposed that this deficiency disease resembles and has a similar basis to Congenital ichthyosiform erythrodema; that is, it is at least in part due to a deficiency of linoleic acid and thereby in the EOS-based delivery of VLCFA to the stratum corneum.

References

External links

* {{UCSC gene info, ALOX12B Fatty acids