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PDBsum entry 1m54
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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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Human cystathionine beta-Synthase is a heme sensor protein. Evidence that the redox sensor is heme and not the vicinal cysteines in the cxxc motif seen in the crystal structure of the truncated enzyme.
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Authors
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S.Taoka,
B.W.Lepore,
O.Kabil,
S.Ojha,
D.Ringe,
R.Banerjee.
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Ref.
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Biochemistry, 2002,
41,
10454-10461.
[DOI no: ]
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PubMed id
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Abstract
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Elevated levels of homocysteine, a sulfur-containing amino acid, are correlated
with increased risk for cardiovascular diseases and Alzheimers disease and with
neural tube defects. The only route for the catabolic removal of homocysteine in
mammals begins with the pyridoxal phosphate- (PLP-) dependent beta-replacement
reaction catalyzed by cystathionine beta-synthase. The enzyme has a b-type heme
with unusual spectroscopic properties but as yet unknown function. The human
enzyme has a modular organization and can be cleaved into an N-terminal
catalytic core, which retains both the heme and PLP-binding sites and is highly
active, and a C-terminal regulatory domain, where the allosteric activator
S-adenosylmethionine is presumed to bind. Studies with the isolated recombinant
enzyme and in transformed human liver cells indicate that the enzyme is
approximately 2-fold more active under oxidizing conditions. In addition to
heme, the enzyme contains a CXXC oxidoreductase motif that could, in principle,
be involved in redox sensing. In this study, we have examined the role of heme
versus the vicinal thiols in modulating the redox responsiveness of the enzyme.
Deletion of the heme domain leads to loss of redox sensitivity. In contrast,
substitution of either cysteine with a non-redox-active amino acid does not
affect the responsiveness of the enzyme to reductants. We also report the
crystal structure of the catalytic core of the enzyme in which the vicinal
cysteines are reduced without any discernible differences in the remainder of
the protein. The structure of the catalytic core is compared to those of other
members of the fold II family of PLP-dependent enzymes and provides insights
into active site residues that may be important in interacting with the
substrates and intermediates.
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Secondary reference #1
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Title
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Structure of human cystathionine beta-Synthase: a unique pyridoxal 5'-Phosphate-Dependent heme protein.
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Authors
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M.Meier,
M.Janosik,
V.Kery,
J.P.Kraus,
P.Burkhard.
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Ref.
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EMBO J, 2001,
20,
3910-3916.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1 Transsulfuration pathway.
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Figure 3.
Figure 3 Structural details of CBS. (A) The active site region
of CBS (gray) in a superposition with the active site of OASS
(green). The sequences as well as the structure of the two
enzymes are very similar. A superposition of the 25 structurally
most conserved residues yields an r.m.s.d. of 1.6 Å of their C[
 ]positions.
The substrate analog of OASS methionine indicates the probable
binding mode of the first substrate serine and also the region
where the second substrate homocysteine is expected to bind. (B)
The heme binding site of CBS with heme in green and the
surrounding residues in gray. The two residues His65 and Cys52
are the ligands to the heme iron (dark red). The difference
density for the cofactor is shown in red contoured at 3.5  .
(C) The oxidoreductase motif in ball-and-stick representation
and (D) in a superposition with the structure of glutaredoxin.
The structure of CBS is in gray, the one of glutaredoxin in
green. The overall topology is very similar, but the active site
motif in CBS is switched to the other helix compared with
glutaredoxin.
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The above figures are
reproduced from the cited reference
which is an Open Access publication published by Macmillan Publishers Ltd
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