* 151570

LEUKOTRIENE A4 HYDROLASE; LTA4H


HGNC Approved Gene Symbol: LTA4H

Cytogenetic location: 12q23.1     Genomic coordinates (GRCh38): 12:96,000,753-96,043,520 (from NCBI)


TEXT

Cloning and Expression

Leukotrienes are a group of bioactive compounds that play important roles in immediate hyposensitivity reactions and inflammation. Minami et al. (1987) reported the full-length cDNA and complete primary structure of human LTA4 hydrolase. This was the first report of the molecular cloning of an enzyme involved in the biosynthesis of eicosanoids. Funk et al. (1987) isolated a cDNA clone corresponding to leukotriene A4 hydrolase from a human lung lambda-gt11 expression library by immunoscreening with a polyclonal antiserum. Several additional clones from human lung and placenta cDNA lambda-gt11 libraries were obtained by plaque hybridization with the (32)P-labeled lung cDNA clone. One of the clones had an insert of 1,910 basepairs containing a complete protein-coding region. From the deduced primary structure, leukotriene A4 hydrolase is a 610-amino acid protein with a calculated molecular weight of 69,140.

Mancini and Evans (1995) cloned the gene for this enzyme, which is a bifunctional amino peptidase and epoxide hydrolase, from a placental lambda phage genomic library. Based on the chromosome localization and genomic DNA analysis, LTA4 hydrolase was determined to be a single-copy gene. Primer-extension analysis demonstrated that the transcription initiation site of the mRNA is 151 nucleotides upstream of the initiator ATG.


Gene Structure

Mancini and Evans (1995) determined that the LTA4H gene is greater than 35 kb in length and contains 19 exons ranging in size from 24 to 312 bp. The introns range in size from 0.26 to 5.7 kb.


Mapping

By fluorescence in situ hybridization, Mancini and Evans (1995) localized the LTA4H gene to 12q22.


Gene Function

Qiu et al. (2006) reported increased mRNA and protein levels of 5-LO (152390), FLAP (603700), 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.

Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B4 (LTB4). LTA4H also possesses aminopeptidase activity, the physiologic substrate of which Snelgrove et al. (2010) identified as the neutrophil chemoattractant proline-glycine-proline (PGP). PGP is a biomarker for chronic obstructive pulmonary disease (COPD; 606963) and is implicated in neutrophil persistence in the lung. In acute neutrophil-driven inflammation, PGP was degraded by LTA4H, which faciliated the resolution of inflammation. In contrast, cigarette smoke, a major risk factor for the development of COPD, selectively inhibited LTA4H aminopeptidase activity, which led to the accumulation of PGP and neutrophils. The studies of Snelgrove et al. (2010) implied that therapeutic strategies inhibiting LTA4H to prevent LTB4 generation may not reduce neutrophil recruitment because of elevated levels of PGP.


Molecular Genetics

Variants of the gene ALOX5AP (603700), which encodes arachidonate 5-lipoxygenase-activating protein, are associated with risk of myocardial infarction (see 608557) (Helgadottir et al., 2004). Helgadottir et al. (2006) showed that a haplotype spanning the LTA4H gene, which encodes leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggested that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also showed that the haplotype designated HapK confers a modest relative risk (1.16) in European Americans, but it confers a 3-fold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Helgadottir et al. (2006) found that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.

Given the altered balance of pro- and antiinflammatory eicosanoids in zebrafish with Lta4h mutations (see ANIMAL MODEL), Tobin et al. (2010) hypothesized that LTA4H polymorphisms may alter the response to human mycobacterial infections that cause tuberculosis (TB; see 607948) and leprosy (see 609888). Comparison of 692 Vietnamese HIV-seronegative pulmonary and meningeal TB patients with 759 healthy controls revealed fewer heterozygotes at each of 6 LTA4H SNPs (rs1978331, rs17677715, rs2247570, rs2660898, rs2660845, and rs2540475) in TB patients. Comparison of frequencies of heterozygotes versus homozygotes among TB patients and controls yielded odds ratios (ORs) less than 1 at all 6 SNPs. Adjusting for multiple comparisons, association of heterozygosity with lower incidence of TB was significant at rs1978331 and rs2660898 (P = 0.011 and 0.0003, respectively, after Bonferroni correction), the 2 SNPs intragenic in LTA4H with common minor allele frequencies. Among 53 meningeal TB patients heterozygous at both rs1978331 and rs2660898, only 4% died within 300 days after diagnosis. In contrast, mortality was 16% among 156 meningeal TB patients homozygous at these SNPs. Evaluation of 335 paucibacillary leprosy patients, 121 multibacillary (MB) leprosy patients with erythema nodosum leprosum (ENL), and 443 MB leprosy patients without ENL from Nepal showed that LTA4H heterozygosity at rs1978331 and rs2660898 was significantly associated with a lower incidence of MB leprosy without ENL (OR = 0.62 and P = 0.001 for rs1978331, and OR = 0.70 and P = 0.021 for rs2660898). Tobin et al. (2010) concluded that LTA4H heterozygosity is associated with protection from TB infection, lower mortality among patients with severe TB infection, and protection from development of severe leprosy disease among exposed individuals. They proposed that LTA4H heterozygosity may reflect an optimal balance, or rheostat mechanism, of pro- and antiinflammatory eicosanoids (i.e., LTB4 and LXA4, respectively), and that modulation of lipoxins, informed by LTA4H genotypes, may result in better outcomes for patients with TB meningitis.

Behr et al. (2010) reviewed several studies implicating stimulation of antiinflammatory molecules and inhibition of autophagy by virulent mycobacteria as a means to evade the host immune system.


Animal Model

Using a forward genetic screen with mutagenized zebrafish, Tobin et al. (2010) identified mutants with differential susceptibility to Mycobacterium marinum (Mm). Hypersusceptible mutants had a mutation in Lta4h, but the phenotype was associated not with reduced production of Ltb4, but with increased production of an antiinflammatory eicosanoid, lipoxin, and reduced production of Tnf (191160) and decreased neutrophil migration early after Mm infection. Tobin et al. (2010) concluded that the reduced inflammation resulting from the Lta4h mutation leads to increased Mm proliferation.


REFERENCES

  1. Behr, M., Schurr, E., Gros, P. TB: screening for responses to a vile visitor. Cell 140: 615-618, 2010. [PubMed: 20211131, related citations] [Full Text]

  2. Funk, C. D., Radmark, O., Fu, J. Y., Matsumoto, T., Jornvall, H., Shimizu, T., Samuelsson, B. Molecular cloning and amino acid sequence of leukotriene A(4) hydrolase. Proc. Nat. Acad. Sci. 84: 6677-6681, 1987. [PubMed: 2821541, related citations] [Full Text]

  3. Helgadottir, A., Manolescu, A., Helgason, A., Thorleifsson, G., Thorsteinsdottir, U., Gudbjartsson, D. F., Gretarsdottir, S., Magnusson, K. P., Gudmundsson, G., Hicks, A., Jonsson, T., Grant, S. F. A., and 19 others. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nature Genet. 38: 68-74, 2006. [PubMed: 16282974, related citations] [Full Text]

  4. Helgadottir, A., Manolescu, A., Thorleifsson, G., Gretarsdottir, S., Jonsdottir, H., Thorsteinsdottir, U., Samani, N. J., Gudmundsson, G., Grant, S. F. A., Thorgeirsson, G., Sveinbjornsdottir, S., Valdimarsson, E. M., and 14 others. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nature Genet. 36: 233-239, 2004. [PubMed: 14770184, related citations] [Full Text]

  5. Mancini, J. A., Evans, J. F. Cloning and characterization of the human leukotriene A-4 hydrolase gene. Europ. J. Biochem. 231: 65-71, 1995. [PubMed: 7628486, related citations] [Full Text]

  6. Minami, M., Ohno, S., Kawasaki, H., Radmark, O., Samuelsson, B., Jornvall, H., Shimizu, T., Seyama, Y., Suzuki, K. Molecular cloning of a cDNA coding for human leukotriene A(4) hydrolase: complete primary structure of an enzyme involved in eicosanoid synthesis. J. Biol. Chem. 262: 13873-13876, 1987. [PubMed: 3654641, related citations]

  7. 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]

  8. Snelgrove, R. J., Jackson, P. L., Hardison, M. T., Noerager, B. D., Kinloch, A., Gagger, A., Shastry, S., Rowe, S. M., Shim, Y. M., Hussell, T., Blalock, J. E. A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330: 90-94, 2010. [PubMed: 20813919, images, related citations] [Full Text]

  9. Tobin, D. M., Vary, J. C., Jr., Ray, J. P., Walsh, G. S., Dunstan, S. J., Bang, N. D., Hagge, D. A., Khadge, S., King, M.-C., Hawn, T. R., Moens, C. B., Ramakrishnan, L. The Ita4h locus modulates susceptibility to Mycobacterial infection in zebrafish and humans. Cell 140: 717-730, 2010. [PubMed: 20211140, images, related citations] [Full Text]


Ada Hamosh - updated : 11/2/2010
Paul J. Converse - updated : 3/23/2010
Cassandra L. Kniffin - updated : 6/8/2006
Creation Date:
Victor A. McKusick : 12/1/1987
alopez : 11/05/2010
terry : 11/2/2010
mgross : 3/25/2010
terry : 3/23/2010
wwang : 6/26/2006
ckniffin : 6/8/2006
alopez : 1/9/2006
alopez : 12/1/2005
terry : 12/1/2005
terry : 6/18/1998
terry : 5/22/1996
mark : 9/27/1995
carol : 1/8/1993
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/27/1989
marie : 3/25/1988

* 151570

LEUKOTRIENE A4 HYDROLASE; LTA4H


HGNC Approved Gene Symbol: LTA4H

Cytogenetic location: 12q23.1     Genomic coordinates (GRCh38): 12:96,000,753-96,043,520 (from NCBI)


TEXT

Cloning and Expression

Leukotrienes are a group of bioactive compounds that play important roles in immediate hyposensitivity reactions and inflammation. Minami et al. (1987) reported the full-length cDNA and complete primary structure of human LTA4 hydrolase. This was the first report of the molecular cloning of an enzyme involved in the biosynthesis of eicosanoids. Funk et al. (1987) isolated a cDNA clone corresponding to leukotriene A4 hydrolase from a human lung lambda-gt11 expression library by immunoscreening with a polyclonal antiserum. Several additional clones from human lung and placenta cDNA lambda-gt11 libraries were obtained by plaque hybridization with the (32)P-labeled lung cDNA clone. One of the clones had an insert of 1,910 basepairs containing a complete protein-coding region. From the deduced primary structure, leukotriene A4 hydrolase is a 610-amino acid protein with a calculated molecular weight of 69,140.

Mancini and Evans (1995) cloned the gene for this enzyme, which is a bifunctional amino peptidase and epoxide hydrolase, from a placental lambda phage genomic library. Based on the chromosome localization and genomic DNA analysis, LTA4 hydrolase was determined to be a single-copy gene. Primer-extension analysis demonstrated that the transcription initiation site of the mRNA is 151 nucleotides upstream of the initiator ATG.


Gene Structure

Mancini and Evans (1995) determined that the LTA4H gene is greater than 35 kb in length and contains 19 exons ranging in size from 24 to 312 bp. The introns range in size from 0.26 to 5.7 kb.


Mapping

By fluorescence in situ hybridization, Mancini and Evans (1995) localized the LTA4H gene to 12q22.


Gene Function

Qiu et al. (2006) reported increased mRNA and protein levels of 5-LO (152390), FLAP (603700), 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.

Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B4 (LTB4). LTA4H also possesses aminopeptidase activity, the physiologic substrate of which Snelgrove et al. (2010) identified as the neutrophil chemoattractant proline-glycine-proline (PGP). PGP is a biomarker for chronic obstructive pulmonary disease (COPD; 606963) and is implicated in neutrophil persistence in the lung. In acute neutrophil-driven inflammation, PGP was degraded by LTA4H, which faciliated the resolution of inflammation. In contrast, cigarette smoke, a major risk factor for the development of COPD, selectively inhibited LTA4H aminopeptidase activity, which led to the accumulation of PGP and neutrophils. The studies of Snelgrove et al. (2010) implied that therapeutic strategies inhibiting LTA4H to prevent LTB4 generation may not reduce neutrophil recruitment because of elevated levels of PGP.


Molecular Genetics

Variants of the gene ALOX5AP (603700), which encodes arachidonate 5-lipoxygenase-activating protein, are associated with risk of myocardial infarction (see 608557) (Helgadottir et al., 2004). Helgadottir et al. (2006) showed that a haplotype spanning the LTA4H gene, which encodes leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggested that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also showed that the haplotype designated HapK confers a modest relative risk (1.16) in European Americans, but it confers a 3-fold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Helgadottir et al. (2006) found that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.

Given the altered balance of pro- and antiinflammatory eicosanoids in zebrafish with Lta4h mutations (see ANIMAL MODEL), Tobin et al. (2010) hypothesized that LTA4H polymorphisms may alter the response to human mycobacterial infections that cause tuberculosis (TB; see 607948) and leprosy (see 609888). Comparison of 692 Vietnamese HIV-seronegative pulmonary and meningeal TB patients with 759 healthy controls revealed fewer heterozygotes at each of 6 LTA4H SNPs (rs1978331, rs17677715, rs2247570, rs2660898, rs2660845, and rs2540475) in TB patients. Comparison of frequencies of heterozygotes versus homozygotes among TB patients and controls yielded odds ratios (ORs) less than 1 at all 6 SNPs. Adjusting for multiple comparisons, association of heterozygosity with lower incidence of TB was significant at rs1978331 and rs2660898 (P = 0.011 and 0.0003, respectively, after Bonferroni correction), the 2 SNPs intragenic in LTA4H with common minor allele frequencies. Among 53 meningeal TB patients heterozygous at both rs1978331 and rs2660898, only 4% died within 300 days after diagnosis. In contrast, mortality was 16% among 156 meningeal TB patients homozygous at these SNPs. Evaluation of 335 paucibacillary leprosy patients, 121 multibacillary (MB) leprosy patients with erythema nodosum leprosum (ENL), and 443 MB leprosy patients without ENL from Nepal showed that LTA4H heterozygosity at rs1978331 and rs2660898 was significantly associated with a lower incidence of MB leprosy without ENL (OR = 0.62 and P = 0.001 for rs1978331, and OR = 0.70 and P = 0.021 for rs2660898). Tobin et al. (2010) concluded that LTA4H heterozygosity is associated with protection from TB infection, lower mortality among patients with severe TB infection, and protection from development of severe leprosy disease among exposed individuals. They proposed that LTA4H heterozygosity may reflect an optimal balance, or rheostat mechanism, of pro- and antiinflammatory eicosanoids (i.e., LTB4 and LXA4, respectively), and that modulation of lipoxins, informed by LTA4H genotypes, may result in better outcomes for patients with TB meningitis.

Behr et al. (2010) reviewed several studies implicating stimulation of antiinflammatory molecules and inhibition of autophagy by virulent mycobacteria as a means to evade the host immune system.


Animal Model

Using a forward genetic screen with mutagenized zebrafish, Tobin et al. (2010) identified mutants with differential susceptibility to Mycobacterium marinum (Mm). Hypersusceptible mutants had a mutation in Lta4h, but the phenotype was associated not with reduced production of Ltb4, but with increased production of an antiinflammatory eicosanoid, lipoxin, and reduced production of Tnf (191160) and decreased neutrophil migration early after Mm infection. Tobin et al. (2010) concluded that the reduced inflammation resulting from the Lta4h mutation leads to increased Mm proliferation.


REFERENCES

  1. Behr, M., Schurr, E., Gros, P. TB: screening for responses to a vile visitor. Cell 140: 615-618, 2010. [PubMed: 20211131] [Full Text: https://doi.org/10.1016/j.cell.2010.02.030]

  2. Funk, C. D., Radmark, O., Fu, J. Y., Matsumoto, T., Jornvall, H., Shimizu, T., Samuelsson, B. Molecular cloning and amino acid sequence of leukotriene A(4) hydrolase. Proc. Nat. Acad. Sci. 84: 6677-6681, 1987. [PubMed: 2821541] [Full Text: https://doi.org/10.1073/pnas.84.19.6677]

  3. Helgadottir, A., Manolescu, A., Helgason, A., Thorleifsson, G., Thorsteinsdottir, U., Gudbjartsson, D. F., Gretarsdottir, S., Magnusson, K. P., Gudmundsson, G., Hicks, A., Jonsson, T., Grant, S. F. A., and 19 others. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nature Genet. 38: 68-74, 2006. [PubMed: 16282974] [Full Text: https://doi.org/10.1038/ng1692]

  4. Helgadottir, A., Manolescu, A., Thorleifsson, G., Gretarsdottir, S., Jonsdottir, H., Thorsteinsdottir, U., Samani, N. J., Gudmundsson, G., Grant, S. F. A., Thorgeirsson, G., Sveinbjornsdottir, S., Valdimarsson, E. M., and 14 others. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nature Genet. 36: 233-239, 2004. [PubMed: 14770184] [Full Text: https://doi.org/10.1038/ng1311]

  5. Mancini, J. A., Evans, J. F. Cloning and characterization of the human leukotriene A-4 hydrolase gene. Europ. J. Biochem. 231: 65-71, 1995. [PubMed: 7628486] [Full Text: https://doi.org/10.1111/j.1432-1033.1995.tb20671.x]

  6. Minami, M., Ohno, S., Kawasaki, H., Radmark, O., Samuelsson, B., Jornvall, H., Shimizu, T., Seyama, Y., Suzuki, K. Molecular cloning of a cDNA coding for human leukotriene A(4) hydrolase: complete primary structure of an enzyme involved in eicosanoid synthesis. J. Biol. Chem. 262: 13873-13876, 1987. [PubMed: 3654641]

  7. 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] [Full Text: https://doi.org/10.1073/pnas.0602414103]

  8. Snelgrove, R. J., Jackson, P. L., Hardison, M. T., Noerager, B. D., Kinloch, A., Gagger, A., Shastry, S., Rowe, S. M., Shim, Y. M., Hussell, T., Blalock, J. E. A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330: 90-94, 2010. [PubMed: 20813919] [Full Text: https://doi.org/10.1126/science.1190594]

  9. Tobin, D. M., Vary, J. C., Jr., Ray, J. P., Walsh, G. S., Dunstan, S. J., Bang, N. D., Hagge, D. A., Khadge, S., King, M.-C., Hawn, T. R., Moens, C. B., Ramakrishnan, L. The Ita4h locus modulates susceptibility to Mycobacterial infection in zebrafish and humans. Cell 140: 717-730, 2010. [PubMed: 20211140] [Full Text: https://doi.org/10.1016/j.cell.2010.02.013]


Contributors:
Ada Hamosh - updated : 11/2/2010
Paul J. Converse - updated : 3/23/2010
Cassandra L. Kniffin - updated : 6/8/2006

Creation Date:
Victor A. McKusick : 12/1/1987

Edit History:
alopez : 11/05/2010
terry : 11/2/2010
mgross : 3/25/2010
terry : 3/23/2010
wwang : 6/26/2006
ckniffin : 6/8/2006
alopez : 1/9/2006
alopez : 12/1/2005
terry : 12/1/2005
terry : 6/18/1998
terry : 5/22/1996
mark : 9/27/1995
carol : 1/8/1993
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/27/1989
marie : 3/25/1988