* 152390

ARACHIDONATE 5-LIPOXYGENASE; ALOX5


Alternative titles; symbols

5-LIPOXYGENASE; LOG5; 5-LO


HGNC Approved Gene Symbol: ALOX5

Cytogenetic location: 10q11.21     Genomic coordinates (GRCh38): 10:45,374,216-45,446,117 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
10q11.21 {Asthma, diminished response to antileukotriene treatment in} 600807 AD 3
{Atherosclerosis, susceptibility to} 3

TEXT

Description

The leukotrienes constitute a group of arachidonic acid-derived compounds with biologic activities suggesting important roles in inflammation and immediate hypersensitivity. The enzyme 5-lipoxygenase (EC 1.13.11.34) catalyzes 2 reactions in the formation of leukotrienes (Matsumoto et al., 1988).


Cloning and Expression

Matsumoto et al. (1988) isolated cDNA clones for human lung and placenta 5-lipoxygenase and deduced the complete amino acid sequence of the enzyme. From the deduced primary structure, the gene appears to code a 673-amino acid protein with a calculated molecular mass of 77,856. 5-Lipoxygenase has no apparent sequence homology with leukotriene A(4) hydrolase (LTA4H; 151570), one of the next enzymes in the arachidonic acid cascade.

Dixon et al. (1988) likewise cloned the cDNA for 5-LO and provided the complete amino acid sequence of the enzyme deduced from the cDNA sequence.


Mapping

By PCR analysis of a human-hamster somatic hybrid DNA panel, Funk et al. (1992) mapped the ALOX5 gene to chromosome 10. Gross (2011) mapped the ALOX5 gene to chromosome 10q11.21 based on an alignment of the ALOX5 sequence (GenBank BC130332) with the genomic sequence (GRCh37).


Gene Function

Voelkel et al. (1996) studied the role of 5-LO in pulmonary hypertension. By immunohistology, they localized 5-LO to macrophages of normal and chronically hypoxic rat lungs and also to vascular endothelial cells in chronically hypoxic lungs only. In situ hybridization of normal and chronically hypoxic lungs demonstrated that 5-LO mRNA is expressed only in the macrophages. Rats hypoxic for 4 weeks developed pulmonary hypertension and showed an increased translocation of lung 5-LO from the cytosol to the membrane fraction, and increased levels of lung 5-LO-activating protein (FLAP; 603700), as demonstrated by Western analysis. MK-886, a FLAP ligand, inhibited the acute angiotensin II and hypoxia-induced pulmonary vasoconstriction in vitro, and the development of chronic hypoxic pulmonary hypertension in rats in vivo. Compared with age-matched 5-LO competent mice, the 5-LO knockout mice developed less right heart hypertrophy. The authors suggested that 5-LO is involved in lung vascular tone regulation and in the development of chronic pulmonary hypertension in hypoxic rodent models.

Human 5-LO contains 3 nuclear localization sequences (NLSs) and a phosphorylation site (ser271) involved in nuclear localization. Luo et al. (2003) found that mutation of either NLS1 or ser271 did not affect 5-LO enzymatic activity in vitro, but decreased synthesis of leukotriene B4 (LTB4) and reduced nuclear localization of 5-LO in transfected mouse fibroblasts. Mutation of all 3 NLSs or of both NLS1 and ser271 inhibited LTB4 synthesis by 90% and abolished nuclear localization. Following stimulation with an ionophore, wildtype 5-LO translocated to the inner membrane of the nuclear envelope and colocalized with exogenously derived arachidonic acid. In contrast, cytosolic 5-LO localized to cytoplasmic and perinuclear membranes. Luo et al. (2003) concluded that the position of 5-LO within the nucleus of resting cells determines the capacity to generate LTB4 upon subsequent activation.

In diseased mouse and human arteries, Zhao et al. (2004) demonstrated that 5-LO-positive macrophages localize to areas of neoangiogenesis and that these cells constitute a main component of aortic aneurysms induced by an atherogenic diet containing cholate in Apoe (107741) -/- mice. 5-LO deficiency markedly attenuated the formation of these aneurysms and was associated with reduced matrix metalloproteinase-2 (MMP2; 120360) activity and diminished plasma macrophage inflammatory protein-1-alpha (CCL3; 182283), but only minimally affected the formation of lipid-rich lesions. The leukotriene LTD4 strongly stimulated expression of CCL3 in macrophages and CXCL2 (139110) in endothelial cells. Zhao et al. (2004) concluded that the 5-LO pathway is linked to hyperlipidemia-dependent inflammation of the arterial wall and to the pathogenesis of aortic aneurysms through a potential chemokine intermediary route.

De Caterina and Zampolli (2004) discussed and diagrammed the main putative roles of 5-lipoxygenase in atherosclerosis.

Qiu et al. (2006) reported increased mRNA and protein levels of 5-LO, FLAP, and LTA4H in 72 human carotid atherosclerotic plaques compared to 6 controls. The proteins colocalized within macrophages in intimal lesions, presumably facilitating enzyme coupling and leukotriene B4 (LTB4) synthesis. There was a correlation between increased levels of 5-LO and LTA4H mRNA and recent or ongoing symptoms of plaque instability. In contrast, 5-LO mRNA was not increased in mouse atherosclerotic plaques, and mouse plaques exhibited segregated cellular expression of 5-LO and LTA4H. These discrepancies indicate important differences and urge caution in translating mouse models into human pathology.

Using HPLC analysis, Rakonjac et al. (2006) showed that CLP (COTL1; 606748) could serve as a scaffold for Ca(2+)-induced 5-LO activity, similar to membranes. In the presence of phosphatidylcholine (membrane), CLP induced increased formation of LTA4 by 5-LO. CLP also increased the ratio of 5-HETE to 5-HPETE. Mutation analysis showed that these effects required trp13, trp75, and trp102 in the ligand-binding loops of the 5-LO beta sandwich. Western blot analysis showed that stimulation of polymorphonuclear cells with Ca(2+) ionophore induced translocation of CLP and 5-LO from the cytosol to the nucleus. Rakonjac et al. (2006) concluded that CLP is relevant to the formation of 5-LO products such as 5-HETE in the cytosol of various cell types and, acting in a complex together with 5-LO and membranes, increases the capacity of 5-LO for leukotriene biosynthesis.

Chu and Pratico (2011) showed that 5-LO regulated the formation of beta-amyloid (APP; 104760) by directly activating CREB (123810), which in turn increased transcription of the proteins involved in the gamma-secretase complex. Studies were performed in human neuroblastoma cells transfected with an Alzheimer disease (AD; 104300)-associated mutation in the APP gene (104760.0008). Pharmacologic inhibition or ALOX5 gene disruption resulted in a significant decrease of beta-amyloid production and gamma-secretase levels. Transgenic mice with the APP mutation had increased levels of 5-LO compared to controls, and treatment with a 5-LO inhibitor decreased beta-amyloid levels in the brain. Alox5-null mice had lower levels of beta-amyloid-40 and -42 species. Chu and Pratico (2011) suggested a novel functional role for 5-LO in regulating endogenous amyloid formation in the central nervous system.


Biochemical Features

ALOX5 activity is short-lived, apparently in part because of an intrinsic instability of the enzyme. Gilbert et al. (2011) identified a lysine-rich region near the C terminus of ALOX5 that conferred instability. Replacement of the sequence KKK at amino acid 653 with the sequence ENL, which is found in other arachidonic acid-metabolizing lipoxygenases, more than doubled the enzyme half-life at 37 degrees C, but did not alter production of leukotriene A4. Gilbert et al. (2011) determined the crystal structure of this mutant, stabilized form of ALOX5 at 2.4-angstrom resolution. The canonical LOX framework contains an N-terminal C2-like domain of about 120 amino acids, which in ALOX5 confers calcium-dependent membrane binding, and a larger catalytic domain. The latter is primarily alpha-helical and harbors the nonheme catalytic iron, which is coordinated by 3 conserved histidines (his367, his372, and his550), as well as C-terminal ile673. In addition, an arched helix, which contains the additional catalytic residues leu420 and phe421, shields access to the catalytic iron and produces a distinctive active-site cavity.


Molecular Genetics

The first committed enzyme in the biosynthetic pathway leading to the production of the leukotrienes is 5-lipoxygenase. In et al. (1997) examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the gene. A family of mutations in the G+C-rich transcription factor binding region was identified, consisting of the deletion of 1, deletion of 2, or addition of 1 zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reported gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P less than 0.05) less effective than the activity driven by the wildtype transcription factor binding region. Electrophoretic mobility shift assays demonstrated the capacity of wildtype and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells. These data were considered consistent with the hypothesis that naturally occurring LOG5 promoter mutations alter transcription factor binding and may play a role in LOG5 gene expression in vivo. No mutations that would modify the amino acid sequence of the protein were identified in the coding region of the LOG5 gene. They speculated that identification of this family of alleles may provide a way to link a given patient's clinical response to treatment modifying the 5-LO pathway and their genotype at the LOG5 locus.

Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase pathway provide a method to identify those patients in whom the products of the ALOX5 pathway (i.e., the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. In et al. (1997) and Silverman et al. (1998) defined a family of DNA sequence variants in the core promoter of the ALOX5 gene associated with diminished promoter-reporter activity in tissue culture. Because expression of ALOX5 is in part transcriptionally regulated, Drazen et al. (1999) reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and drug-treatment responses, i.e., a pharmacogenetic effect of a promoter sequence on treatment responses.

Since atherosclerosis involves arterial inflammation, Dwyer et al. (2004) hypothesized that a polymorphism in the 5-lipoxygenase gene promoter could relate to atherosclerosis in humans and that this effect could interact with the dietary intake of competing 5-lipoxygenase substrates. They found that variant 5-lipoxygenase genotypes (lacking the common allele) in 6.0% of a cohort of 470 healthy, middle-aged women and men from the Los Angeles Atherosclerosis Study. Mean intima-media thickness (IMT) adjusted for age, sex, height, and racial or ethnic group was increased by 80 micro m among carriers of 2 variant alleles, as compared with carriers of the common (wildtype) allele. In multivariate analysis, the increase in IMT among carriers of 2 variant alleles was similar in this cohort to that associated with diabetes, the strongest common cardiovascular risk factor. Increased dietary arachidonic acid significantly enhanced the apparent atherogenic effect of the genotype, whereas increased dietary intake of n-3 fatty acids blunted the effect. Finally, the plasma level of C-reactive protein (CRP; 123260), a marker of inflammation, was increased by a factor of 2 among carriers of 2 variant alleles as compared with that among carriers of the common allele. The variants of ALOX tested involved the number of tandem Sp1 binding motifs (5-prime-GGGCGG-3-prime) in the promoter. Variant alleles involved deletions (1 or 2) or additions (1, 2, or 3) of Sp1 motifs to the 5 tandem motifs in the common allele.

Assimes et al. (2008) genotyped 7 SNPs in the ALOX5 gene in 1,552 patients with 'clinically significant' coronary artery disease (CAD) and 1,583 controls and identified a nominally significant association (p = 0.002) between the promoter SNP rs12762303 and CAD in Caucasian patients; however, the association could not be reproduced in 9,800 Caucasian and 3,352 African American subjects that included 1,154 and 255 cases of incident coronary heart disease (CHD), respectively. They identified a high correlation between rs12762303 and the Sp1 repeat site in Caucasian and Hispanic subjects. Assimes et al. (2008) found no significant associations between rs12762303 and the mean degree of carotid IMT, dietary intake of various fatty acids on the risk of CHD, and dietary intake of fatty acids on the mean degree of carotid IMT.

By genotyping ALOX5 polymorphisms in 1,916 Ghanaians with sputum-positive pulmonary tuberculosis (TB; see 607948) and in 2,269 healthy but TB-exposed controls, Herb et al. (2008) found that heterozygote carriers of variant (other than 5 repeats) and wildtype (5 repeats) variant number of tandem repeats (VNTR) promoter alleles or of the genomic 760A exonic allele had a higher risk of TB. The association with the exonic allele was stronger in patients infected with an M. africanum strain of tuberculosis. The strongest haplotype association was for the variant VNTR/760A haplotype compared to with the variant VNTR/760G haplotype. Herb et al. (2008) proposed that the association of ALOX5 variants with TB in this population supports evidence from animal models of the importance of 5-LO products in the regulation of immune responses to M. tuberculosis.


Animal Model

Aliberti et al. (2002) found that 5-lo -/- mice had reduced resistance to Toxoplasma gondii infection.

Bafica et al. (2005) found that endothelial cells and macrophages of wildtype mice infected with Mycobacterium tuberculosis produced high levels of the eicosanoids LTB4 and lipoxin A4 (LXA4). Synthesis of LXA4, but not LTB4, was maintained during chronic infection. In contrast, neither eicosanoid was detected above background levels in infected 5-lo -/- mice. Histopathologic and bacteriologic analyses showed that 5-lo -/- mice had enhanced control of tuberculosis infection with fewer bacilli and lower inflammatory infiltration in the lung. After high-dose infection, but not low-dose infection, the normally resistant wildtype mouse strain succumbed more rapidly than the knockout mice. Real-time RT-PCR analysis detected significantly increased expression of Il12b (161561), Ifng (147570), and Nos2 (163730), but not Tnf (191160), in 5-lo -/- mice compared with wildtype mice. ELISA analysis confirmed the expression data for Il12b and Tnf. Administration of a stable LXA4 analog, ATLa2, abrogated the enhanced control of bacterial replication in 5-lo -/- mice, but had no effect on resistance in wildtype mice. Bafica et al. (2005) concluded that the 5-LO-dependent lipoxin production pathway is important in controlling proinflammatory and Th1 immune responses against M. tuberculosis infection. They proposed that 5-LO inhibitors may be useful immunopharmacologic agents for treatment of tuberculosis patients.

Drake et al. (2001) identified a locus on mouse chromosome 6 with pleiotropic effects on adiposity, plasma lipoprotein levels, and bone density. Mehrabian et al. (2005) used an integrative genomics approach to show that the pleiotropic metabolic effects of the chromosome 6 locus could be attributed, at least in part, to the Alox5 gene encoding 5-lipoxygenase. They used both forward and reverse genetic approaches.

Chen et al. (2009) found that Alox5-null mice were resistant to the development of BCR/ABL (see 151410)-induced chronic myeloid leukemia (CML; 608232). Initial cellular studies showed that leukemia stem cells (LSCs) that had been transduced with and expressed BCR/ABL showed upregulation of Alox5 compared to cells that did not express BCR/ABL. Alox5 deficiency caused impairment of the function of LSCs by affecting differentiation, cell division, and survival of long-term LSCs. This resulted in a depletion of LSCs and a failure of CML development. In contrast, Alox5 deficiency did not impair the function of normal hematopoietic stem cells. Further studies indicated that an intact Alox5 pathway was essential for induction of CML by BCR/ABL. Treatment of CML mice with a 5-LO inhibitor also impaired the function of LSCs by affecting long-term LSCs, and prolonged survival. These results demonstrated that a specific target gene can be found in cancer stem cells and that its inhibition can completely inhibit the function of these stem cells.


ALLELIC VARIANTS ( 1 Selected Example):

.0001 ASTHMA, DIMINISHED RESPONSE TO ANTILEUKOTRIENE TREATMENT IN

ATHEROSCLEROSIS, SUSCEPTIBILITY TO
ALOX5, VARIANT PROMOTER SP1 BINDING
  
RCV000015530...

Drazen et al. (1999) found that asthmatics who were carriers of variants in the promoter region of the ALOX5 gene had a diminished response to treatment with antileukotriene drugs, indicating a pharmacogenetic effect of a promoter sequence on treatment responses. Deletion or addition of binding motifs had been found to be associated with altered (reduced) transcription of the ALOX5 gene, as compared with the common allele.

Dwyer et al. (2004) studied carotid artery intima-media thickness in relation to the polymorphism of the promoter region of the ALOX5 gene, specifically the number of tandem Sp1 binding motifs (5-prime-GGGCGG-3-prime). Of 6 alleles (as determined by the method of In et al., 1997), the most frequent allele, accounting for 80.5%, contained 5 of these tandem motifs. Variant alleles involved deletions (1 or 2) or additions (1, 2, or 3) of SP1 motifs to the 5 tandem motifs in the common allele. Variant ALOX5 genotypes identified a subpopulation with increased atherosclerosis. Furthermore, Dwyer et al. (2004) observed diet-gene interactions, suggesting that dietary n-6 polyunsaturated fatty acids promote, whereas marine n-3 fatty acids inhibit, leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation of healthy, middle-aged women and men.


REFERENCES

  1. Aliberti, J., Serhan, C., Sher, A. Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection. J. Exp. Med. 196: 1253-1262, 2002. [PubMed: 12417634, images, related citations] [Full Text]

  2. Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Volcik, K. A., Southwick, A., Tabor, H. K., Hartiala, J., Allayee, H., Grove, M. L., Tabibiazar, R., Sidney, S., Fortmann, S. P., Go, A., Hlatky, M., Iribarren, C., Boerwinkle, E., Myers, R., Risch, N., Quertermous, T. Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease. Hum. Genet. 123: 399-408, 2008. [PubMed: 18369664, related citations] [Full Text]

  3. Bafica, A., Scanga, C. A., Serhan, C., Machado, F., White, S., Sher, A., Aliberti, J. Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. J. Clin. Invest. 115: 1601-1606, 2005. [PubMed: 15931391, images, related citations] [Full Text]

  4. Chen, Y., Hu, Y., Zhang, H., Peng, C., Li, S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genet. 41: 783-792, 2009. [PubMed: 19503090, images, related citations] [Full Text]

  5. Chu, J., Pratico, D. 5-lipoxygenase as an endogenous modulator of amyloid-beta formation in vivo. Ann. Neurol. 69: 34-46, 2011. [PubMed: 21280074, images, related citations] [Full Text]

  6. De Caterina, R., Zampolli, A. From asthma to atherosclerosis--5-lipoxygenase, leukotrienes, and inflammation. New Eng. J. Med. 350: 4-7, 2004. [PubMed: 14702420, related citations] [Full Text]

  7. Dixon, R. A. F., Jones, R. E., Diehl, R. E., Bennett, C. D., Kargman, S., Rouzer, C. A. Cloning of the cDNA for human 5-lipoxygenase. Proc. Nat. Acad. Sci. 85: 416-420, 1988. [PubMed: 3422434, related citations] [Full Text]

  8. Drake, T. A., Schadt, E., Hannani, K., Kabo, J. M., Krass, K., Colinayo, V., Greaser, L. E., III, Goldin, J., Lusis, A. J. Genetic loci determining bone density in mice with diet-induced atherosclerosis. Physiol. Genomics 5: 205-215, 2001. [PubMed: 11328966, related citations] [Full Text]

  9. Drazen, J. M., Yandava, C. N., Dube, L., Szczerback, N., Hippensteel, R., Pillari, A., Israel, E., Schork, N., Silverman, E. S., Katz, D. A., Drajesk, J. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 22: 168-170, 1999. [PubMed: 10369259, related citations] [Full Text]

  10. Dwyer, J. H., Allayee, H., Dwyer, K. M., Fan, J., Wu, H., Mar, R., Lusis, A. J., Mehrabian, M. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. New Eng. J. Med. 350: 29-37, 2004. [PubMed: 14702425, related citations] [Full Text]

  11. Funk, C. D., Funk, L. B., FitzGerald, G. A., Samuelsson, B. Characterization of human 12-lipoxygenase genes. Proc. Nat. Acad. Sci. 89: 3962-3966, 1992. [PubMed: 1570320, related citations] [Full Text]

  12. Gilbert, N. C., Bartlett, S. G., Waight, M. T., Neau, D. B., Boeglin, W. E., Brash, A. R., Newcomer, M. E. The structure of human 5-lipoxygenase. Science 331: 217-219, 2011. [PubMed: 21233389, images, related citations] [Full Text]

  13. Gross, M. B. Personal Communication. Baltimore, Md. 5/17/2011.

  14. Herb, F., Thye, T., Niemann, S., Browne, E. N. L., Chinbuah, M. A., Gyapong, J., Osei, I., Owusu-Dabo, E., Werz, O., Rusch-Gerdes, S., Horstmann, R. D., Meyer, C. G. ALOX5 variants associated with susceptibility to human pulmonary tuberculosis. Hum. Molec. Genet. 17: 1052-1060, 2008. [PubMed: 18174194, related citations] [Full Text]

  15. In, K. H., Asano, K., Beier, D., Grobholz, J., Finn, P. W., Silverman, E. K., Silverman, E. S., Collins, T., Fischer, A. R., Keith, T. P., Serino, K., Kim, S. W., De Sanctis, G. T., Yandava, C., Pillari, A., Rubin, P., Kemp, J., Israel, E., Busse, W., Ledford, D., Murray, J. J., Segal, A., Tinkleman, D., Drazen, J. M. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J. Clin. Invest. 99: 1130-1137, 1997. [PubMed: 9062372, related citations] [Full Text]

  16. Luo, M., Jones, S. M., Peters-Golden, M., Brock, T. G. Nuclear localization of 5-lipoxygenase as a determinant of leukotriene B(4) synthetic capacity. Proc. Nat. Acad. Sci. 100: 12165-12170, 2003. [PubMed: 14530386, images, related citations] [Full Text]

  17. Matsumoto, T., Funk, C. D., Radmark, O., Hoog, J.-O., Jornvall, H., Samuelsson, B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc. Nat. Acad. Sci. 85: 26-30, 1988. Note: Erratum: Proc. Nat. Acad. Sci. 85: 3406 only, 1988. [PubMed: 2829172, related citations] [Full Text]

  18. Mehrabian, M., Allayee, H., Stockton, J., Lum, P. Y., Drake, T. A., Castellani, L. W., Suh, M., Armour, C., Edwards, S., Lamb, J., Lusis, A. J., Schadt, E. E. Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits. Nature Genet. 37: 1224-1233, 2005. Note: Erratum: Nature Genet. 37: 1381 only, 2005. [PubMed: 16200066, related citations] [Full Text]

  19. Qiu, H., Gabrielsen, A., Agardh, H. E., Wan, M., Wetterholm, A., Wong, C.-H., Hedin, U., Swedenborg, J., Hansson, G. K., Samuelsson, B., Paulsson-Berne, G., Haeggstrom, J. Z. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc. Nat. Acad. Sci. 103: 8161-8166, 2006. [PubMed: 16698924, images, related citations] [Full Text]

  20. Rakonjac, M., Fischer, L., Provost, P., Werz, O., Steinhilber, D., Samuelsson, B., Radmark, O. Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A(4) production. Proc. Nat. Acad. Sci. 103: 13150-13155, 2006. [PubMed: 16924104, images, related citations] [Full Text]

  21. Silverman, E. S., Du, J., De Sanctis, G. T., Radmark, O., Samuelson, B., Drazen, J. M., Collins, T. Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. Am. J. Resp. Cell Molec. Biol. 19: 316-323, 1998. [PubMed: 9698605, related citations] [Full Text]

  22. Voelkel, N. F., Tuder, R. M., Wade, K., Hoper, M., Lepley, R. A., Goulet, J. L., Koller, B. H., Fitzpatrick, F. Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats. J. Clin. Invest. 97: 2491-2498, 1996. [PubMed: 8647941, related citations] [Full Text]

  23. Zhao, L., Moos, M. P. W., Grabner, R., Pedrono, F., Fan, J., Kaiser, B., John, N., Schmidt, S., Spanbroek, R., Lotzer, K., Huang, L., Cui, J., Rader, D. J., Evans, J. F., Habenicht, A. J. R., Funk, C. D. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nature Med. 10: 966-973, 2004. [PubMed: 15322539, related citations] [Full Text]


Matthew B. Gross - updated : 5/17/2011
Patricia A. Hartz - updated : 5/10/2011
Cassandra L. Kniffin - updated : 3/15/2011
Paul J. Converse - updated : 12/11/2009
Cassandra L. Kniffin - updated : 8/5/2009
Marla J. F. O'Neill - updated : 10/17/2008
Paul J. Converse - updated : 10/16/2006
Cassandra L. Kniffin - updated : 6/8/2006
Victor A. McKusick - updated : 11/17/2005
Patricia A. Hartz - updated : 10/19/2005
Paul J. Converse - updated : 6/23/2005
Marla J. F. O'Neill - updated : 9/30/2004
Victor A. McKusick - updated : 1/20/2004
Wilson H. Y. Lo - updated : 4/6/2000
Victor A. McKusick - updated : 5/27/1999
Victor A. McKusick - updated : 5/9/1997
Creation Date:
Victor A. McKusick : 2/9/1988
carol : 05/03/2019
carol : 08/30/2013
alopez : 3/11/2013
terry : 2/16/2012
terry : 1/17/2012
mgross : 5/17/2011
terry : 5/10/2011
wwang : 3/30/2011
ckniffin : 3/15/2011
mgross : 1/8/2010
mgross : 1/8/2010
terry : 12/11/2009
terry : 12/11/2009
wwang : 8/18/2009
ckniffin : 8/5/2009
carol : 3/17/2009
wwang : 10/17/2008
mgross : 10/16/2006
wwang : 6/26/2006
ckniffin : 6/8/2006
alopez : 12/6/2005
alopez : 11/21/2005
terry : 11/17/2005
mgross : 10/31/2005
terry : 10/19/2005
mgross : 6/23/2005
carol : 9/30/2004
cwells : 1/22/2004
terry : 1/20/2004
carol : 11/24/2003
carol : 6/15/2000
terry : 4/6/2000
terry : 4/6/2000
terry : 6/9/1999
alopez : 6/1/1999
terry : 5/27/1999
terry : 7/8/1997
alopez : 6/4/1997
alopez : 5/9/1997
alopez : 5/7/1997
carol : 7/6/1992
carol : 6/3/1992
supermim : 3/16/1992
carol : 8/6/1991
supermim : 3/20/1990
ddp : 10/27/1989

* 152390

ARACHIDONATE 5-LIPOXYGENASE; ALOX5


Alternative titles; symbols

5-LIPOXYGENASE; LOG5; 5-LO


HGNC Approved Gene Symbol: ALOX5

Cytogenetic location: 10q11.21     Genomic coordinates (GRCh38): 10:45,374,216-45,446,117 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
10q11.21 {Asthma, diminished response to antileukotriene treatment in} 600807 Autosomal dominant 3
{Atherosclerosis, susceptibility to} 3

TEXT

Description

The leukotrienes constitute a group of arachidonic acid-derived compounds with biologic activities suggesting important roles in inflammation and immediate hypersensitivity. The enzyme 5-lipoxygenase (EC 1.13.11.34) catalyzes 2 reactions in the formation of leukotrienes (Matsumoto et al., 1988).


Cloning and Expression

Matsumoto et al. (1988) isolated cDNA clones for human lung and placenta 5-lipoxygenase and deduced the complete amino acid sequence of the enzyme. From the deduced primary structure, the gene appears to code a 673-amino acid protein with a calculated molecular mass of 77,856. 5-Lipoxygenase has no apparent sequence homology with leukotriene A(4) hydrolase (LTA4H; 151570), one of the next enzymes in the arachidonic acid cascade.

Dixon et al. (1988) likewise cloned the cDNA for 5-LO and provided the complete amino acid sequence of the enzyme deduced from the cDNA sequence.


Mapping

By PCR analysis of a human-hamster somatic hybrid DNA panel, Funk et al. (1992) mapped the ALOX5 gene to chromosome 10. Gross (2011) mapped the ALOX5 gene to chromosome 10q11.21 based on an alignment of the ALOX5 sequence (GenBank BC130332) with the genomic sequence (GRCh37).


Gene Function

Voelkel et al. (1996) studied the role of 5-LO in pulmonary hypertension. By immunohistology, they localized 5-LO to macrophages of normal and chronically hypoxic rat lungs and also to vascular endothelial cells in chronically hypoxic lungs only. In situ hybridization of normal and chronically hypoxic lungs demonstrated that 5-LO mRNA is expressed only in the macrophages. Rats hypoxic for 4 weeks developed pulmonary hypertension and showed an increased translocation of lung 5-LO from the cytosol to the membrane fraction, and increased levels of lung 5-LO-activating protein (FLAP; 603700), as demonstrated by Western analysis. MK-886, a FLAP ligand, inhibited the acute angiotensin II and hypoxia-induced pulmonary vasoconstriction in vitro, and the development of chronic hypoxic pulmonary hypertension in rats in vivo. Compared with age-matched 5-LO competent mice, the 5-LO knockout mice developed less right heart hypertrophy. The authors suggested that 5-LO is involved in lung vascular tone regulation and in the development of chronic pulmonary hypertension in hypoxic rodent models.

Human 5-LO contains 3 nuclear localization sequences (NLSs) and a phosphorylation site (ser271) involved in nuclear localization. Luo et al. (2003) found that mutation of either NLS1 or ser271 did not affect 5-LO enzymatic activity in vitro, but decreased synthesis of leukotriene B4 (LTB4) and reduced nuclear localization of 5-LO in transfected mouse fibroblasts. Mutation of all 3 NLSs or of both NLS1 and ser271 inhibited LTB4 synthesis by 90% and abolished nuclear localization. Following stimulation with an ionophore, wildtype 5-LO translocated to the inner membrane of the nuclear envelope and colocalized with exogenously derived arachidonic acid. In contrast, cytosolic 5-LO localized to cytoplasmic and perinuclear membranes. Luo et al. (2003) concluded that the position of 5-LO within the nucleus of resting cells determines the capacity to generate LTB4 upon subsequent activation.

In diseased mouse and human arteries, Zhao et al. (2004) demonstrated that 5-LO-positive macrophages localize to areas of neoangiogenesis and that these cells constitute a main component of aortic aneurysms induced by an atherogenic diet containing cholate in Apoe (107741) -/- mice. 5-LO deficiency markedly attenuated the formation of these aneurysms and was associated with reduced matrix metalloproteinase-2 (MMP2; 120360) activity and diminished plasma macrophage inflammatory protein-1-alpha (CCL3; 182283), but only minimally affected the formation of lipid-rich lesions. The leukotriene LTD4 strongly stimulated expression of CCL3 in macrophages and CXCL2 (139110) in endothelial cells. Zhao et al. (2004) concluded that the 5-LO pathway is linked to hyperlipidemia-dependent inflammation of the arterial wall and to the pathogenesis of aortic aneurysms through a potential chemokine intermediary route.

De Caterina and Zampolli (2004) discussed and diagrammed the main putative roles of 5-lipoxygenase in atherosclerosis.

Qiu et al. (2006) reported increased mRNA and protein levels of 5-LO, FLAP, and LTA4H in 72 human carotid atherosclerotic plaques compared to 6 controls. The proteins colocalized within macrophages in intimal lesions, presumably facilitating enzyme coupling and leukotriene B4 (LTB4) synthesis. There was a correlation between increased levels of 5-LO and LTA4H mRNA and recent or ongoing symptoms of plaque instability. In contrast, 5-LO mRNA was not increased in mouse atherosclerotic plaques, and mouse plaques exhibited segregated cellular expression of 5-LO and LTA4H. These discrepancies indicate important differences and urge caution in translating mouse models into human pathology.

Using HPLC analysis, Rakonjac et al. (2006) showed that CLP (COTL1; 606748) could serve as a scaffold for Ca(2+)-induced 5-LO activity, similar to membranes. In the presence of phosphatidylcholine (membrane), CLP induced increased formation of LTA4 by 5-LO. CLP also increased the ratio of 5-HETE to 5-HPETE. Mutation analysis showed that these effects required trp13, trp75, and trp102 in the ligand-binding loops of the 5-LO beta sandwich. Western blot analysis showed that stimulation of polymorphonuclear cells with Ca(2+) ionophore induced translocation of CLP and 5-LO from the cytosol to the nucleus. Rakonjac et al. (2006) concluded that CLP is relevant to the formation of 5-LO products such as 5-HETE in the cytosol of various cell types and, acting in a complex together with 5-LO and membranes, increases the capacity of 5-LO for leukotriene biosynthesis.

Chu and Pratico (2011) showed that 5-LO regulated the formation of beta-amyloid (APP; 104760) by directly activating CREB (123810), which in turn increased transcription of the proteins involved in the gamma-secretase complex. Studies were performed in human neuroblastoma cells transfected with an Alzheimer disease (AD; 104300)-associated mutation in the APP gene (104760.0008). Pharmacologic inhibition or ALOX5 gene disruption resulted in a significant decrease of beta-amyloid production and gamma-secretase levels. Transgenic mice with the APP mutation had increased levels of 5-LO compared to controls, and treatment with a 5-LO inhibitor decreased beta-amyloid levels in the brain. Alox5-null mice had lower levels of beta-amyloid-40 and -42 species. Chu and Pratico (2011) suggested a novel functional role for 5-LO in regulating endogenous amyloid formation in the central nervous system.


Biochemical Features

ALOX5 activity is short-lived, apparently in part because of an intrinsic instability of the enzyme. Gilbert et al. (2011) identified a lysine-rich region near the C terminus of ALOX5 that conferred instability. Replacement of the sequence KKK at amino acid 653 with the sequence ENL, which is found in other arachidonic acid-metabolizing lipoxygenases, more than doubled the enzyme half-life at 37 degrees C, but did not alter production of leukotriene A4. Gilbert et al. (2011) determined the crystal structure of this mutant, stabilized form of ALOX5 at 2.4-angstrom resolution. The canonical LOX framework contains an N-terminal C2-like domain of about 120 amino acids, which in ALOX5 confers calcium-dependent membrane binding, and a larger catalytic domain. The latter is primarily alpha-helical and harbors the nonheme catalytic iron, which is coordinated by 3 conserved histidines (his367, his372, and his550), as well as C-terminal ile673. In addition, an arched helix, which contains the additional catalytic residues leu420 and phe421, shields access to the catalytic iron and produces a distinctive active-site cavity.


Molecular Genetics

The first committed enzyme in the biosynthetic pathway leading to the production of the leukotrienes is 5-lipoxygenase. In et al. (1997) examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the gene. A family of mutations in the G+C-rich transcription factor binding region was identified, consisting of the deletion of 1, deletion of 2, or addition of 1 zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reported gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P less than 0.05) less effective than the activity driven by the wildtype transcription factor binding region. Electrophoretic mobility shift assays demonstrated the capacity of wildtype and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells. These data were considered consistent with the hypothesis that naturally occurring LOG5 promoter mutations alter transcription factor binding and may play a role in LOG5 gene expression in vivo. No mutations that would modify the amino acid sequence of the protein were identified in the coding region of the LOG5 gene. They speculated that identification of this family of alleles may provide a way to link a given patient's clinical response to treatment modifying the 5-LO pathway and their genotype at the LOG5 locus.

Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase pathway provide a method to identify those patients in whom the products of the ALOX5 pathway (i.e., the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. In et al. (1997) and Silverman et al. (1998) defined a family of DNA sequence variants in the core promoter of the ALOX5 gene associated with diminished promoter-reporter activity in tissue culture. Because expression of ALOX5 is in part transcriptionally regulated, Drazen et al. (1999) reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and drug-treatment responses, i.e., a pharmacogenetic effect of a promoter sequence on treatment responses.

Since atherosclerosis involves arterial inflammation, Dwyer et al. (2004) hypothesized that a polymorphism in the 5-lipoxygenase gene promoter could relate to atherosclerosis in humans and that this effect could interact with the dietary intake of competing 5-lipoxygenase substrates. They found that variant 5-lipoxygenase genotypes (lacking the common allele) in 6.0% of a cohort of 470 healthy, middle-aged women and men from the Los Angeles Atherosclerosis Study. Mean intima-media thickness (IMT) adjusted for age, sex, height, and racial or ethnic group was increased by 80 micro m among carriers of 2 variant alleles, as compared with carriers of the common (wildtype) allele. In multivariate analysis, the increase in IMT among carriers of 2 variant alleles was similar in this cohort to that associated with diabetes, the strongest common cardiovascular risk factor. Increased dietary arachidonic acid significantly enhanced the apparent atherogenic effect of the genotype, whereas increased dietary intake of n-3 fatty acids blunted the effect. Finally, the plasma level of C-reactive protein (CRP; 123260), a marker of inflammation, was increased by a factor of 2 among carriers of 2 variant alleles as compared with that among carriers of the common allele. The variants of ALOX tested involved the number of tandem Sp1 binding motifs (5-prime-GGGCGG-3-prime) in the promoter. Variant alleles involved deletions (1 or 2) or additions (1, 2, or 3) of Sp1 motifs to the 5 tandem motifs in the common allele.

Assimes et al. (2008) genotyped 7 SNPs in the ALOX5 gene in 1,552 patients with 'clinically significant' coronary artery disease (CAD) and 1,583 controls and identified a nominally significant association (p = 0.002) between the promoter SNP rs12762303 and CAD in Caucasian patients; however, the association could not be reproduced in 9,800 Caucasian and 3,352 African American subjects that included 1,154 and 255 cases of incident coronary heart disease (CHD), respectively. They identified a high correlation between rs12762303 and the Sp1 repeat site in Caucasian and Hispanic subjects. Assimes et al. (2008) found no significant associations between rs12762303 and the mean degree of carotid IMT, dietary intake of various fatty acids on the risk of CHD, and dietary intake of fatty acids on the mean degree of carotid IMT.

By genotyping ALOX5 polymorphisms in 1,916 Ghanaians with sputum-positive pulmonary tuberculosis (TB; see 607948) and in 2,269 healthy but TB-exposed controls, Herb et al. (2008) found that heterozygote carriers of variant (other than 5 repeats) and wildtype (5 repeats) variant number of tandem repeats (VNTR) promoter alleles or of the genomic 760A exonic allele had a higher risk of TB. The association with the exonic allele was stronger in patients infected with an M. africanum strain of tuberculosis. The strongest haplotype association was for the variant VNTR/760A haplotype compared to with the variant VNTR/760G haplotype. Herb et al. (2008) proposed that the association of ALOX5 variants with TB in this population supports evidence from animal models of the importance of 5-LO products in the regulation of immune responses to M. tuberculosis.


Animal Model

Aliberti et al. (2002) found that 5-lo -/- mice had reduced resistance to Toxoplasma gondii infection.

Bafica et al. (2005) found that endothelial cells and macrophages of wildtype mice infected with Mycobacterium tuberculosis produced high levels of the eicosanoids LTB4 and lipoxin A4 (LXA4). Synthesis of LXA4, but not LTB4, was maintained during chronic infection. In contrast, neither eicosanoid was detected above background levels in infected 5-lo -/- mice. Histopathologic and bacteriologic analyses showed that 5-lo -/- mice had enhanced control of tuberculosis infection with fewer bacilli and lower inflammatory infiltration in the lung. After high-dose infection, but not low-dose infection, the normally resistant wildtype mouse strain succumbed more rapidly than the knockout mice. Real-time RT-PCR analysis detected significantly increased expression of Il12b (161561), Ifng (147570), and Nos2 (163730), but not Tnf (191160), in 5-lo -/- mice compared with wildtype mice. ELISA analysis confirmed the expression data for Il12b and Tnf. Administration of a stable LXA4 analog, ATLa2, abrogated the enhanced control of bacterial replication in 5-lo -/- mice, but had no effect on resistance in wildtype mice. Bafica et al. (2005) concluded that the 5-LO-dependent lipoxin production pathway is important in controlling proinflammatory and Th1 immune responses against M. tuberculosis infection. They proposed that 5-LO inhibitors may be useful immunopharmacologic agents for treatment of tuberculosis patients.

Drake et al. (2001) identified a locus on mouse chromosome 6 with pleiotropic effects on adiposity, plasma lipoprotein levels, and bone density. Mehrabian et al. (2005) used an integrative genomics approach to show that the pleiotropic metabolic effects of the chromosome 6 locus could be attributed, at least in part, to the Alox5 gene encoding 5-lipoxygenase. They used both forward and reverse genetic approaches.

Chen et al. (2009) found that Alox5-null mice were resistant to the development of BCR/ABL (see 151410)-induced chronic myeloid leukemia (CML; 608232). Initial cellular studies showed that leukemia stem cells (LSCs) that had been transduced with and expressed BCR/ABL showed upregulation of Alox5 compared to cells that did not express BCR/ABL. Alox5 deficiency caused impairment of the function of LSCs by affecting differentiation, cell division, and survival of long-term LSCs. This resulted in a depletion of LSCs and a failure of CML development. In contrast, Alox5 deficiency did not impair the function of normal hematopoietic stem cells. Further studies indicated that an intact Alox5 pathway was essential for induction of CML by BCR/ABL. Treatment of CML mice with a 5-LO inhibitor also impaired the function of LSCs by affecting long-term LSCs, and prolonged survival. These results demonstrated that a specific target gene can be found in cancer stem cells and that its inhibition can completely inhibit the function of these stem cells.


ALLELIC VARIANTS 1 Selected Example):

.0001   ASTHMA, DIMINISHED RESPONSE TO ANTILEUKOTRIENE TREATMENT IN

ATHEROSCLEROSIS, SUSCEPTIBILITY TO
ALOX5, VARIANT PROMOTER SP1 BINDING
SNP: rs59439148, ClinVar: RCV000015530, RCV000015531

Drazen et al. (1999) found that asthmatics who were carriers of variants in the promoter region of the ALOX5 gene had a diminished response to treatment with antileukotriene drugs, indicating a pharmacogenetic effect of a promoter sequence on treatment responses. Deletion or addition of binding motifs had been found to be associated with altered (reduced) transcription of the ALOX5 gene, as compared with the common allele.

Dwyer et al. (2004) studied carotid artery intima-media thickness in relation to the polymorphism of the promoter region of the ALOX5 gene, specifically the number of tandem Sp1 binding motifs (5-prime-GGGCGG-3-prime). Of 6 alleles (as determined by the method of In et al., 1997), the most frequent allele, accounting for 80.5%, contained 5 of these tandem motifs. Variant alleles involved deletions (1 or 2) or additions (1, 2, or 3) of SP1 motifs to the 5 tandem motifs in the common allele. Variant ALOX5 genotypes identified a subpopulation with increased atherosclerosis. Furthermore, Dwyer et al. (2004) observed diet-gene interactions, suggesting that dietary n-6 polyunsaturated fatty acids promote, whereas marine n-3 fatty acids inhibit, leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation of healthy, middle-aged women and men.


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Contributors:
Matthew B. Gross - updated : 5/17/2011
Patricia A. Hartz - updated : 5/10/2011
Cassandra L. Kniffin - updated : 3/15/2011
Paul J. Converse - updated : 12/11/2009
Cassandra L. Kniffin - updated : 8/5/2009
Marla J. F. O'Neill - updated : 10/17/2008
Paul J. Converse - updated : 10/16/2006
Cassandra L. Kniffin - updated : 6/8/2006
Victor A. McKusick - updated : 11/17/2005
Patricia A. Hartz - updated : 10/19/2005
Paul J. Converse - updated : 6/23/2005
Marla J. F. O'Neill - updated : 9/30/2004
Victor A. McKusick - updated : 1/20/2004
Wilson H. Y. Lo - updated : 4/6/2000
Victor A. McKusick - updated : 5/27/1999
Victor A. McKusick - updated : 5/9/1997

Creation Date:
Victor A. McKusick : 2/9/1988

Edit History:
carol : 05/03/2019
carol : 08/30/2013
alopez : 3/11/2013
terry : 2/16/2012
terry : 1/17/2012
mgross : 5/17/2011
terry : 5/10/2011
wwang : 3/30/2011
ckniffin : 3/15/2011
mgross : 1/8/2010
mgross : 1/8/2010
terry : 12/11/2009
terry : 12/11/2009
wwang : 8/18/2009
ckniffin : 8/5/2009
carol : 3/17/2009
wwang : 10/17/2008
mgross : 10/16/2006
wwang : 6/26/2006
ckniffin : 6/8/2006
alopez : 12/6/2005
alopez : 11/21/2005
terry : 11/17/2005
mgross : 10/31/2005
terry : 10/19/2005
mgross : 6/23/2005
carol : 9/30/2004
cwells : 1/22/2004
terry : 1/20/2004
carol : 11/24/2003
carol : 6/15/2000
terry : 4/6/2000
terry : 4/6/2000
terry : 6/9/1999
alopez : 6/1/1999
terry : 5/27/1999
terry : 7/8/1997
alopez : 6/4/1997
alopez : 5/9/1997
alopez : 5/7/1997
carol : 7/6/1992
carol : 6/3/1992
supermim : 3/16/1992
carol : 8/6/1991
supermim : 3/20/1990
ddp : 10/27/1989