1h19: Difference between revisions

Revision as of 13:56, 21 February 2008

STRUCTURE OF [E271Q] LEUKOTRIENE A4 HYDROLASE

OverviewOverview

Leukotriene A(4) hydrolase/aminopeptidase is a bifunctional zinc metalloenzyme that converts the fatty acid epoxide leukotriene A(4) into leukotriene B(4), a potent chemoattractant and immune-modulating lipid mediator. Recently, the structure of leukotriene A(4) hydrolase revealed that Glu-271, which belongs to a conserved GXMEN motif in the M1 family of zinc peptidases, and Gln-136 are located at the active site. Here we report that mutagenetic replacements of Glu-271, but not Gln-136, abrogate both catalytic activities of leukotriene A(4) hydrolase. Furthermore, the 2.1 A crystal structure of [E271Q]leukotriene A(4) hydrolase revealed minimal conformational changes that could not explain the loss of enzyme function. We propose that the carboxylate of Glu-271 participates in an acid-induced opening of the epoxide moiety of leukotriene A(4) and formation of a carbocation intermediate. Moreover, Glu-271 appears to act as an N-terminal recognition site and may potentially stabilize the transition-state during turnover of peptides, a property that most likely pertains to all members of the M1 family of zinc aminopeptidases. Hence, Glu-271 is a unique example of an amino acid, which has dual and separate functions in two different catalytic reactions, involving lipid and peptide substrates, respectively.

About this StructureAbout this Structure

1H19 is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Active as Leukotriene-A(4) hydrolase, with EC number 3.3.2.6 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms., Rudberg PC, Tholander F, Thunnissen MM, Haeggstrom JZ, J Biol Chem. 2002 Jan 11;277(2):1398-404. Epub 2001 Oct 23. PMID:11675384

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 ==Overview==
-Leukotriene A(4) hydrolase/aminopeptidase is a bifunctional zinc, metalloenzyme that converts the fatty acid epoxide leukotriene A(4) into, leukotriene B(4), a potent chemoattractant and immune-modulating lipid, mediator. Recently, the structure of leukotriene A(4) hydrolase revealed, that Glu-271, which belongs to a conserved GXMEN motif in the M1 family of, zinc peptidases, and Gln-136 are located at the active site. Here we, report that mutagenetic replacements of Glu-271, but not Gln-136, abrogate, both catalytic activities of leukotriene A(4) hydrolase. Furthermore, the, 2.1 A crystal structure of [E271Q]leukotriene A(4) hydrolase revealed, minimal conformational changes that could not explain the loss of enzyme, function. We propose that the carboxylate of Glu-271 participates in an, acid-induced opening of the epoxide moiety of leukotriene A(4) and, formation of a carbocation intermediate. Moreover, Glu-271 appears to act, as an N-terminal recognition site and may potentially stabilize the, transition-state during turnover of peptides, a property that most likely, pertains to all members of the M1 family of zinc aminopeptidases. Hence, Glu-271 is a unique example of an amino acid, which has dual and separate, functions in two different catalytic reactions, involving lipid and, peptide substrates, respectively.
+Leukotriene A(4) hydrolase/aminopeptidase is a bifunctional zinc metalloenzyme that converts the fatty acid epoxide leukotriene A(4) into leukotriene B(4), a potent chemoattractant and immune-modulating lipid mediator. Recently, the structure of leukotriene A(4) hydrolase revealed that Glu-271, which belongs to a conserved GXMEN motif in the M1 family of zinc peptidases, and Gln-136 are located at the active site. Here we report that mutagenetic replacements of Glu-271, but not Gln-136, abrogate both catalytic activities of leukotriene A(4) hydrolase. Furthermore, the 2.1 A crystal structure of [E271Q]leukotriene A(4) hydrolase revealed minimal conformational changes that could not explain the loss of enzyme function. We propose that the carboxylate of Glu-271 participates in an acid-induced opening of the epoxide moiety of leukotriene A(4) and formation of a carbocation intermediate. Moreover, Glu-271 appears to act as an N-terminal recognition site and may potentially stabilize the transition-state during turnover of peptides, a property that most likely pertains to all members of the M1 family of zinc aminopeptidases. Hence, Glu-271 is a unique example of an amino acid, which has dual and separate functions in two different catalytic reactions, involving lipid and peptide substrates, respectively.
 ==About this Structure==
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 [[Category: Leukotriene-A(4) hydrolase]]
 [[Category: Single protein]]
-[[Category: Haeggstrom, J.Z.]]
+[[Category: Haeggstrom, J Z.]]
-[[Category: Rudberg, P.C.]]
+[[Category: Rudberg, P C.]]
 [[Category: Tholander, F.]]
-[[Category: Thunnissen, M.M.G.M.]]
+[[Category: Thunnissen, M M.G M.]]
 [[Category: ACY]]
 [[Category: IMD]]
@@ Line 27: / Line 27: @@
 [[Category: metalloprotease]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 09:45:04 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:56:17 2008''