Leukotriene A-4 hydrolase (LTA4H)
The protein contains 611 amino acids for an estimated molecular weight of 69285 Da.
Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the proinflammatory mediator leukotriene B4 (LTB4) (PubMed:11917124, PubMed:12207002, PubMed:15078870, PubMed:18804029, PubMed:1897988, PubMed:1975494, PubMed:2244921). Has also aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides (PubMed:20813919, PubMed:18804029). In addition to its proinflammatory EH activity, may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase (PREPL) (PubMed:20813919, PubMed:24591641). Involved also in the biosynthesis of resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid mediators that show potent anti-inflammatory and pro-resolving actions (PubMed:21206090). (updated: Feb. 10, 2021)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs45630737 |
Biological Process
Arachidonic acid metabolic process
Cellular lipid metabolic process
Cellular protein metabolic process
Inflammatory response
Leukotriene biosynthetic process
Leukotriene metabolic process
Long-chain fatty acid biosynthetic process
Neutrophil degranulation
Peptide catabolic process
Small molecule metabolic process
The reference OMIM entry for this protein is 151570
Leukotriene a4 hydrolase; lta4h
CLONING
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, ... More on the omim web site
Feb. 16, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 151570 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed