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PDBsum entry 1bj4
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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 crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy.
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Authors
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S.B.Renwick,
K.Snell,
U.Baumann.
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Ref.
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Structure, 1998,
6,
1105-1116.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Serine hydroxymethyltransferase (SHMT) is a ubiquitous enzyme found
in all prokaryotes and eukaryotes. As an enzyme of the thymidylate synthase
metabolic cycle, SHMT catalyses the retro-aldol cleavage of serine to glycine,
with the resulting hydroxymethyl group being transferred to tetrahydrofolate to
form 5, 10-methylene-tetrahydrofolate. The latter is the major source of
one-carbon units in metabolism. Elevated SHMT activity has been shown to be
coupled to the increased demand for DNA synthesis in rapidly proliferating
cells, particularly tumour cells. Consequently, the central role of SHMT in
nucleotide biosynthesis makes it an attractive target for cancer chemotherapy.
RESULTS: We have solved the crystal structure of human cytosolic SHMT by
multiple isomorphous replacement to 2.65 A resolution. The monomer has a fold
typical for alpha class pyridoxal 5'-phosphate (PLP) dependent enzymes. The
tetramer association is best described as a 'dimer of dimers' where residues
from both subunits of one 'tight' dimer contribute to the active site.
CONCLUSIONS: The crystal structure shows the evolutionary relationship between
SHMT and other alpha class PLP-dependent enzymes, as the fold is highly
conserved. Many of the results of site-directed mutagenesis studies can easily
be rationalised or re-interpreted in light of the structure presented here. For
example, His 151 is not the catalytic base, contrary to the findings of others.
A mechanism for the cleavage of serine to glycine and formaldehyde is proposed.
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Figure 7.
Figure 7. Steroview comparisons of the active sites from
different PLP-dependent enzymes. (a) Overlay of the active sites
of aspartate aminotransferase (AAT; cyan) and SHMT (green). (b)
Overlay of ornithine decarboxylase (ORD; cyan) and SHMT (green).
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1998,
6,
1105-1116)
copyright 1998.
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