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PDBsum entry 1c3c
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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 structure of adenylosuccinate lyase, An enzyme with dual activity in the de novo purine biosynthetic pathway.
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Authors
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E.A.Toth,
T.O.Yeates.
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Ref.
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Structure, 2000,
8,
163-174.
[DOI no: ]
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PubMed id
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Abstract
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Background: Adenylosuccinate lyase is an enzyme that plays a critical role in
both cellular replication and metabolism via its action in the de novo purine
biosynthetic pathway. Adenylosuccinate lyase is the only enzyme in this pathway
to catalyze two separate reactions, enabling it to participate in the addition
of a nitrogen at two different positions in adenosine monophosphate. Both
reactions catalyzed by adenylosuccinate lyase involve the beta-elimination of
fumarate. Enzymes that catalyze this type of reaction belong to a superfamily,
the members of which are homotetramers. Because adenylosuccinate lyase plays an
integral part in maintaining proper cellular metabolism, mutations in the human
enzyme can have severe clinical consequences, including mental retardation with
autistic features. Results: The 1.8 A crystal structure of adenylosuccinate
lyase from Thermotoga maritima has been determined by multiwavelength anomalous
dispersion using the selenomethionine-substituted enzyme. The fold of the
monomer is reminiscent of other members of the beta-elimination superfamily.
However, its active tetrameric form exhibits striking differences in active-site
architecture and cleft size. Conclusions: This first structure of an
adenylosuccinate lyase reveals that, along with the catalytic base (His141) and
the catalytic acid (His68), Gln212 and Asn270 might play a vital role in
catalysis by properly orienting the succinyl moiety of the substrates. We
propose a model for the dual activity of adenylosuccinate lyase: a single 180
degrees bond rotation must occur in the substrate between the first and second
enzymatic reactions. Modeling of the pathogenic human S413P mutation indicates
that the mutation destabilizes the enzyme by disrupting the C-terminal extension.
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Figure 8.
Figure 8. Mapping of the S413P human ASL mutation to the T.
maritima ASL structure. The residue singled out by directional
profiles (Asp406) is colored green. The residue singled out by
the extensible threading calculator (ETC) method (Thr404) is
colored cyan. The C-terminal extension is colored red. This
figure was generated using RIBBONS [36].
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2000,
8,
163-174)
copyright 2000.
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