Europe PMC
Nothing Special   »   [go: up one dir, main page]

Europe PMC requires Javascript to function effectively.

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page.

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

Leukotriene A4 hydrolase: mapping of a henicosapeptide involved in mechanism-based inactivation.

Author information

Affiliations

  • 1. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
      Authors
    • Mueller MJ 1
    (1 author)

ORCIDs linked to this article

Proceedings of the National Academy of Sciences of the United States of America, 01 Aug 1995, 92(18):8383-8387
https://doi.org/10.1073/pnas.92.18.8383 PMID: 7667299 PMCID: PMC41161

Free full text in Europe PMC

Abstract 

Leukotriene A4 (LTA4) hydrolase [7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9 ,11,14-tetraenoate hydrolase; EC 3.3.2.6] is a bifunctional zinc metalloenzyme which converts LTA4 into the chemotactic agent leukotriene B4 (LTB4). Suicide inactivation, a typical feature of LTA4 hydrolase/aminopeptidase, occurs via an irreversible, apparently mechanism-based, covalent binding of LTA4 to the protein in a 1:1 stoichiometry. Differential lysine-specific peptide mapping of unmodified and suicide-inactivated LTA4 hydrolase has been used to identify a henicosapeptide, encompassing the amino acid residues 365-385 of human LTA4 hydrolase, which is involved in the binding of LTA4, LTA4 methyl ester, and LTA4 ethyl ester to the native enzyme. A modified form of this peptide, generated by lysine-specific digestion of LTA4 hydrolase inactivated by LTA4 ethyl ester, could be isolated for complete Edman degradation. The sequence analysis revealed a gap at position 14, which shows that binding of the leukotriene epoxide had occurred via Tyr-378 in LTA4 hydrolase. Inactivation of the epoxide hydrolase and the aminopeptidase activity was accompanied by a proportionate modification of the peptide. Furthermore, both enzyme inactivation and peptide modification could be prevented by preincubation of LTA4 hydrolase with the competitive inhibitor bestatin, which demonstrates that the henicosapeptide contains functional elements of the active site(s). It may now be possible to clarify the molecular mechanisms underlying suicide inactivation and epoxide hydrolysis by site-directed mutagenesis combined with structural analysis of the lipid molecule, covalently bound to the peptide.

Free full text 

Logo of pnasLink to Publisher's site
Proc Natl Acad Sci U S A. 1995 Aug 29; 92(18): 8383–8387.
PMCID: PMC41161
PMID: 7667299

Leukotriene A4 hydrolase: mapping of a henicosapeptide involved in mechanism-based inactivation.

M J Mueller, A Wetterholm, M Blomster, H Jörnvall, B Samuelsson, and J Z Haeggström
Author information Copyright and License information Disclaimer

Abstract

Leukotriene A4 (LTA4) hydrolase [7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9 ,11,14-tetraenoate hydrolase; EC 3.3.2.6] is a bifunctional zinc metalloenzyme which converts LTA4 into the chemotactic agent leukotriene B4 (LTB4). Suicide inactivation, a typical feature of LTA4 hydrolase/aminopeptidase, occurs via an irreversible, apparently mechanism-based, covalent binding of LTA4 to the protein in a 1:1 stoichiometry. Differential lysine-specific peptide mapping of unmodified and suicide-inactivated LTA4 hydrolase has been used to identify a henicosapeptide, encompassing the amino acid residues 365-385 of human LTA4 hydrolase, which is involved in the binding of LTA4, LTA4 methyl ester, and LTA4 ethyl ester to the native enzyme. A modified form of this peptide, generated by lysine-specific digestion of LTA4 hydrolase inactivated by LTA4 ethyl ester, could be isolated for complete Edman degradation. The sequence analysis revealed a gap at position 14, which shows that binding of the leukotriene epoxide had occurred via Tyr-378 in LTA4 hydrolase. Inactivation of the epoxide hydrolase and the aminopeptidase activity was accompanied by a proportionate modification of the peptide. Furthermore, both enzyme inactivation and peptide modification could be prevented by preincubation of LTA4 hydrolase with the competitive inhibitor bestatin, which demonstrates that the henicosapeptide contains functional elements of the active site(s). It may now be possible to clarify the molecular mechanisms underlying suicide inactivation and epoxide hydrolysis by site-directed mutagenesis combined with structural analysis of the lipid molecule, covalently bound to the peptide.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
 
icon of scanned page 8383
8383
icon of scanned page 8384
8384
icon of scanned page 8385
8385
icon of scanned page 8386
8386
icon of scanned page 8387
8387
 

Images in this article

Fig. 1
Fig. 1
on p.8384
Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Ford-Hutchinson AW. Leukotriene B4 in inflammation. Crit Rev Immunol. 1990;10(1):1–12. [Abstract] [Google Scholar]
  • Arand M, Grant DF, Beetham JK, Friedberg T, Oesch F, Hammock BD. Sequence similarity of mammalian epoxide hydrolases to the bacterial haloalkane dehalogenase and other related proteins. Implication for the potential catalytic mechanism of enzymatic epoxide hydrolysis. FEBS Lett. 1994 Feb 7;338(3):251–256. [Abstract] [Google Scholar]
  • Haeggström JZ, Wetterholm A, Vallee BL, Samuelsson B. Leukotriene A4 hydrolase: an epoxide hydrolase with peptidase activity. Biochem Biophys Res Commun. 1990 Nov 30;173(1):431–437. [Abstract] [Google Scholar]
  • Minami M, Ohishi N, Mutoh H, Izumi T, Bito H, Wada H, Seyama Y, Toh H, Shimizu T. Leukotriene A4 hydrolase is a zinc-containing aminopeptidase. Biochem Biophys Res Commun. 1990 Dec 14;173(2):620–626. [Abstract] [Google Scholar]
  • Griffin KJ, Gierse J, Krivi G, Fitzpatrick FA. Opioid peptides are substrates for the bifunctional enzyme LTA4 hydrolase/aminopeptidase. Prostaglandins. 1992 Sep;44(3):251–257. [Abstract] [Google Scholar]
  • Orning L, Gierse JK, Fitzpatrick FA. The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity. J Biol Chem. 1994 Apr 15;269(15):11269–11273. [Abstract] [Google Scholar]
  • Orning L, Krivi G, Fitzpatrick FA. Leukotriene A4 hydrolase. Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes. J Biol Chem. 1991 Jan 25;266(3):1375–1378. [Abstract] [Google Scholar]
  • Orning L, Krivi G, Bild G, Gierse J, Aykent S, Fitzpatrick FA. Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril. J Biol Chem. 1991 Sep 5;266(25):16507–16511. [Abstract] [Google Scholar]
  • Haeggström JZ, Wetterholm A, Medina JF, Samuelsson B. Leukotriene A4 hydrolase: structural and functional properties of the active center. J Lipid Mediat. 1993 Mar-Apr;6(1-3):1–13. [Abstract] [Google Scholar]
  • McGee J, Fitzpatrick F. Enzymatic hydration of leukotriene A4. Purification and characterization of a novel epoxide hydrolase from human erythrocytes. J Biol Chem. 1985 Oct 15;260(23):12832–12837. [Abstract] [Google Scholar]
  • Evans JF, Nathaniel DJ, Zamboni RJ, Ford-Hutchinson AW. Leukotriene A3. A poor substrate but a potent inhibitor of rat and human neutrophil leukotriene A4 hydrolase. J Biol Chem. 1985 Sep 15;260(20):10966–10970. [Abstract] [Google Scholar]
  • Sun FF, McGuire JC. Metabolism of arachidonic acid by human neutrophils. Characterization of the enzymatic reactions that lead to the synthesis of leukotriene B4. Biochim Biophys Acta. 1984 Jun 6;794(1):56–64. [Abstract] [Google Scholar]
  • Ohishi N, Izumi T, Minami M, Kitamura S, Seyama Y, Ohkawa S, Terao S, Yotsumoto H, Takaku F, Shimizu T. Leukotriene A4 hydrolase in the human lung. Inactivation of the enzyme with leukotriene A4 isomers. J Biol Chem. 1987 Jul 25;262(21):10200–10205. [Abstract] [Google Scholar]
  • Orning L, Jones DA, Fitzpatrick FA. Mechanism-based inactivation of leukotriene A4 hydrolase during leukotriene B4 formation by human erythrocytes. J Biol Chem. 1990 Sep 5;265(25):14911–14916. [Abstract] [Google Scholar]
  • Orning L, Gierse J, Duffin K, Bild G, Krivi G, Fitzpatrick FA. Mechanism-based inactivation of leukotriene A4 hydrolase/aminopeptidase by leukotriene A4. Mass spectrometric and kinetic characterization. J Biol Chem. 1992 Nov 15;267(32):22733–22739. [Abstract] [Google Scholar]
  • Evans JF, Kargman S. Bestatin inhibits covalent coupling of [3H]LTA4 to human leukocyte LTA4 hydrolase. FEBS Lett. 1992 Feb 3;297(1-2):139–142. [Abstract] [Google Scholar]
  • Haeggström J, Rådmark O, Fitzpatrick FA. Leukotriene A4-hydrolase activity in guinea pig and human liver. Biochim Biophys Acta. 1985 Jul 9;835(2):378–384. [Abstract] [Google Scholar]
  • Wetterholm A, Medina JF, Rådmark O, Shapiro R, Haeggström JZ, Vallee BL, Samuelsson B. Recombinant mouse leukotriene A4 hydrolase: a zinc metalloenzyme with dual enzymatic activities. Biochim Biophys Acta. 1991 Oct 25;1080(2):96–102. [Abstract] [Google Scholar]
  • Wetterholm A, Macchia L, Haeggström JZ. Zinc and other divalent cations inhibit purified leukotriene A4 hydrolase and leukotriene B4 biosynthesis in human polymorphonuclear leukocytes. Arch Biochem Biophys. 1994 Jun;311(2):263–271. [Abstract] [Google Scholar]
  • Wetterholm A, Haeggström JZ. Leukotriene A4 hydrolase: an anion activated peptidase. Biochim Biophys Acta. 1992 Feb 12;1123(3):275–281. [Abstract] [Google Scholar]
  • Malfroy B, Kado-Fong H, Gros C, Giros B, Schwartz JC, Hellmiss R. Molecular cloning and amino acid sequence of rat kidney aminopeptidase M: a member of a super family of zinc-metallohydrolases. Biochem Biophys Res Commun. 1989 May 30;161(1):236–241. [Abstract] [Google Scholar]
  • Vallee BL, Auld DS. Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry. 1990 Jun 19;29(24):5647–5659. [Abstract] [Google Scholar]
  • Mueller MJ, Samuelsson B, Haeggström JZ. Chemical modification of leukotriene A4 hydrolase. Indications for essential tyrosyl and arginyl residues at the active site. Biochemistry. 1995 Mar 21;34(11):3536–3543. [Abstract] [Google Scholar]
Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Full text links 

Read article at publisher's site: https://doi.org/10.1073/pnas.92.18.8383

Read article for free, from open access legal sources, via Unpaywall: http://www.pnas.org/content/92/18/8383.full.pdfUnpaywall

Citations & impact 

Impact metrics

23
Citations
Jump to Citations
2
Data citations
Jump to Data

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/42048438
Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/42048438

Smart citations by scite.ai
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
Explore citation contexts and check if this article has been supported or disputed.
https://scite.ai/reports/10.1073/pnas.92.18.8383

Supporting
Mentioning
Contrasting
1
38
0

Article citations

Go to all (23) article citations

Data 

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.