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PDBsum entry 1h7o
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The X-Ray structure of yeast 5-Aminolaevulinic acid dehydratase complexed with substrate and three inhibitors.
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Authors
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P.T.Erskine,
R.Newbold,
A.A.Brindley,
S.P.Wood,
P.M.Shoolingin-Jordan,
M.J.Warren,
J.B.Cooper.
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Ref.
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J Mol Biol, 2001,
312,
133-141.
[DOI no: ]
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PubMed id
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Abstract
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The structures of 5-aminolaevulinic acid dehydratase (ALAD) complexed with
substrate (5-aminolaevulinic acid) and three inhibitors: laevulinic acid,
succinylacetone and 4-keto-5-aminolaevulinic acid, have been solved at high
resolution. The ligands all bind by forming a covalent link with Lys263 at the
active site. The structures define the interactions made by one of the two
substrate moieties that bind to the enzyme during catalysis. All of the
inhibitors induce a significant ordering of the flap covering the active site.
Succinylacetone appears to be unique by inducing a number of conformational
changes in loops covering the active site, which may be important for
understanding the co-operative properties of ALAD enzymes. Succinylacetone is
produced in large amounts by patients suffering from the hereditary disease type
I tyrosinaemia and its potent inhibition of ALAD also has implications for the
pathology of this disease. The most intriguing result is that obtained with
4-keto-5-amino-hexanoic acid, which seems to form a stable carbinolamine
intermediate with Lys263. It appears that we have defined the structure of an
intermediate of Schiff base formation that the substrate forms upon binding to
the P-site of the enzyme.
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Figure 4.
Figure 4. The electron density for each of the ALAD
ligands bound to Lys263: (a) substrate ALA at 1.7 Å res-
olution; (b) laevulinic acid (LA) at 1.6 Å resolution; (c)
succinylacetone (SA) at 2.0 Å resolution; and (d) 4-keto-
5-amino-hexanoic acid (KAH) at 1.64 Å resolution. All
maps are contoured at 1.0 rms. The Lys263 side-chain
can be seen behind the inhibitor moiety. The two confor-
mers adopted by ALA and LA are coloured slightly
different shades of green in (a) and (b).
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Figure 6.
Figure 6. The electron density
for 4-keto-5-amino-hexanoic acid
(KAH) contoured at 1.2 rms show-
ing the residues it interacts with.
The inhibitor has been modelled
as a carbinolamine intermediate
(labelled KAT).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2001,
312,
133-141)
copyright 2001.
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