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PDBsum entry 1t5a
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References listed in PDB file
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Key reference
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Title
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Structural basis for tumor pyruvate kinase m2 allosteric regulation and catalysis.
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Authors
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J.D.Dombrauckas,
B.D.Santarsiero,
A.D.Mesecar.
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Ref.
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Biochemistry, 2005,
44,
9417-9429.
[DOI no: ]
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PubMed id
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Abstract
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Four isozymes of pyruvate kinase are differentially expressed in human tissue.
Human pyruvate kinase isozyme M2 (hPKM2) is expressed in early fetal tissues and
is progressively replaced by the other three isozymes, M1, R, and L, immediately
after birth. In most cancer cells, hPKM2 is once again expressed to promote
tumor cell proliferation. Because of its almost ubiquitous presence in cancer
cells, hPKM2 has been designated as tumor specific PK-M2, and its presence in
human plasma is currently being used as a molecular marker for the diagnosis of
various cancers. The X-ray structure of human hPKM2 complexed with Mg(2+), K(+),
the inhibitor oxalate, and the allosteric activator fructose 1,6-bisphosphate
(FBP) has been determined to a resolution of 2.82 A. The active site of hPKM2 is
in a partially closed conformation most likely resulting from a ligand-induced
domain closure promoted by the binding of FBP. In all four subunits of the
enzyme tetramer, a conserved water molecule is observed on the 2-si face of the
prospective enolate and supports the hypothesis that a proton-relay system is
acting as the proton donor of the reaction (1). Significant structural
differences among the human M2, rabbit muscle M1, and the human R isozymes are
observed, especially in the orientation of the FBP-activating loop, which is in
a closed conformation when FBP is bound. The structural differences observed
between the PK isozymes could potentially be exploited as unique structural
templates for the design of allosteric drugs against the disease states
associated with the various PK isozymes, especially cancer and nonspherocytic
hemolytic anemia.
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