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PDBsum entry 3chp
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References listed in PDB file
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Key reference
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Title
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Synthesis of glutamic acid analogs as potent inhibitors of leukotriene a4 hydrolase.
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Authors
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T.A.Kirkland,
M.Adler,
J.G.Bauman,
M.Chen,
J.Z.Haeggström,
B.King,
M.J.Kochanny,
A.M.Liang,
L.Mendoza,
G.B.Phillips,
M.Thunnissen,
L.Trinh,
M.Whitlow,
B.Ye,
H.Ye,
J.Parkinson,
W.J.Guilford.
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Ref.
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Bioorg Med Chem Lett, 2008,
16,
4963-4983.
[DOI no: ]
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PubMed id
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Abstract
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Leukotriene B(4) (LTB(4)) is a potent pro-inflammatory mediator that has been
implicated in the pathogenesis of multiple diseases, including psoriasis,
inflammatory bowel disease, multiple sclerosis and asthma. As a method to
decrease the level of LTB(4) and possibly identify novel treatments, inhibitors
of the LTB(4) biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have
been explored. Here we describe the discovery of a potent inhibitor of LTA(4)-h,
arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2.
Analogs of 4f are then described, focusing on compounds that are both active and
stable in whole blood. This effort culminated in the identification of amino
alcohol 12a and amino ester 6b which meet these criteria.
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Secondary reference #1
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Title
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Crystal structure of human leukotriene a(4) hydrolase, A bifunctional enzyme in inflammation.
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Authors
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M.M.Thunnissen,
P.Nordlund,
J.Z.Haeggström.
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Ref.
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Nat Struct Biol, 2001,
8,
131-135.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. Overall and domain structure of LTA4H. a, Ribbon
diagram of the tertiary structure of LTA4H. The N-terminal
domain is colored blue (residues 1 -207), the catalytic domain
green (residues 208 -450) and the C-terminal domain red
(residues 461 -610). A loop containing a highly conserved
Pro-rich motif p451-G-  -P-P-x-k-P-x-y460
( ,
hydrophobic residues Phe, Tyr, Trp, Ile, Leu, Val, Met and Ala;
capital letter, identical amino acids; small letter, conserved
in chemistry) is shown in yellow. The figure was created using
MolScript27, Glr (L. Esser and J. Deisenhofer, pers. comm.) and
POV-Ray (http://www.povray.org). b, Stereo view of the
superposition of the C  trace
of the catalytic domain (red) on thermolysin (blue). c, Stereo
view of a 2F[o] - F[c] electron density map for the active site,
including bestatin, contoured at 1.1  .
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Figure 4.
Figure 4. Proposed reaction mechanism for the epoxide hydrolase
activity of LTA4H. The carboxylate of LTA[4] is bound to Arg
563 and Lys 565. The catalytic Zn2+ acts as a Lewis acid and
activates the epoxide to form a carbocation intermediate
according to an S[N]1 reaction. Water is added at C12 in a
stereospecific manner directed by Asp 375. The double bond
geometry is controlled by the binding conformation of LTA[4].
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The above figures are
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
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Secondary reference #2
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Title
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Crystal structures of leukotriene a4 hydrolase in complex with captopril and two competitive tight-Binding inhibitors.
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Authors
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M.M.Thunnissen,
B.Andersson,
B.Samuelsson,
C.H.Wong,
J.Haeggström.
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Ref.
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Faseb J, 2002,
16,
1648-1650.
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PubMed id
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Secondary reference #3
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Title
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Leukotriene a4 hydrolase: selective abrogation of leukotriene b4 formation by mutation of aspartic acid 375.
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Authors
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P.C.Rudberg,
F.Tholander,
M.M.Thunnissen,
B.Samuelsson,
J.Z.Haeggstrom.
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Ref.
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Proc Natl Acad Sci U S A, 2002,
99,
4215-4220.
[DOI no: ]
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PubMed id
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Figure 2.
Fig. 2. Structure of the mutant [D375N]LTA4H. (A)
Superpositioning of wild-type LTA4H and [D375N]LTA4H. Stereo
image of selected residues of the active site of wild-type LTA4H
complexed with bestatin superimposed onto [D375N]LTA4H. The
wild-type and [D375N]LTA4H structures are shown in pale blue and
red, respectively. The Zn2+ ions, the bestatin, and water
molecules of wild type (pale blue) and [D375N]LTA4H (red) are
also shown. The image shows very subtle conformational changes
and thus a high degree of structural preservation after mutation
of Asp-375 to Asn-375. See text for further discussion. The
figure was generated with SWISS-PDBVIEWER (33) and POV-RAY
(http://www.povray.org). (B) Comparison of the hydrogen-bonding
networks around Asp-375 and Asn-375. The side chain of Asn-375
is indicated in red. Likewise the interactions with His-139,
Tyr-267, and two water molecules of Asp-375 and Asn-375 are
depicted in dotted black and red lines, respectively. Distances
are given in Å.
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Figure 4.
Fig. 4. Role of Asp-375 in the epoxide hydrolase
reaction. LTA[4] is modeled into the L-shaped hydrophobic pocket
with its  -end
pointing to the bottom of the cavity. After activation and
opening of the epoxide by the Zn2+ and Glu-271 according to an
S[N]1 mechanism, a carbocation is formed whose charge will be
delocalized over the conjugated triene system. At C12, a
nucleophilic attack can be mediated by means of Asp-375 to
produce the 12R-hydroxyl group of LTB[4] (for further details
see text). For an alternative role of Glu-271 involving an ester
intermediate, see ref. 8.
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Secondary reference #4
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Title
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Leukotriene a4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates
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Authors
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P.C.Rudberg,
F.O.T.Tholander,
M.Andberg,
M.M.G.M.Thunnissen,
J.Z.Haeggstrom.
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Ref.
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j mol biol, 2004,
279,
27376.
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