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PDBsum entry 1l6y
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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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Species-Specific inhibition of porphobilinogen synthase by 4-Oxosebacic acid.
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Authors
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E.K.Jaffe,
J.Kervinen,
J.Martins,
F.Stauffer,
R.Neier,
A.Wlodawer,
A.Zdanov.
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Ref.
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J Biol Chem, 2002,
277,
19792-19799.
[DOI no: ]
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PubMed id
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Abstract
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Porphobilinogen synthase (PBGS) catalyzes the condensation of two molecules of
5-aminolevulinic acid (ALA), an essential step in tetrapyrrole biosynthesis.
4-Oxosebacic acid (4-OSA) and 4,7-dioxosebacic acid (4,7-DOSA) are bisubstrate
reaction intermediate analogs for PBGS. We show that 4-OSA is an active
site-directed irreversible inhibitor for Escherichia coli PBGS, whereas human,
pea, Pseudomonas aeruginosa, and Bradyrhizobium japonicum PBGS are insensitive
to inhibition by 4-OSA. Some variants of human PBGS (engineered to resemble E.
coli PBGS) have increased sensitivity to inactivation by 4-OSA, suggesting a
structural basis for the specificity. The specificity of 4-OSA as a PBGS
inhibitor is significantly narrower than that of 4,7-DOSA. Comparison of the
crystal structures for E. coli PBGS inactivated by 4-OSA versus 4,7-DOSA shows
significant variation in the half of the inhibitor that mimics the second
substrate molecule (A-side ALA). Compensatory changes occur in the structure of
the active site lid, which suggests that similar changes normally occur to
accommodate numerous hybridization changes that must occur at C3 of A-side ALA
during the PBGS-catalyzed reaction. A comparison of these with other PBGS
structures identifies highly conserved active site water molecules, which are
isolated from bulk solvent and implicated as proton acceptors in the
PBGS-catalyzed reaction.
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Figure 4.
Fig. 4. A stereo diagram of the 4-OSA inactivated E. coli
PBGS dimer. The two monomers are shown in blue and magenta, Zn2+
is dark green, Mg2+ is orange, and the active site lid is
yellow. The two active site lysine residues are shown
(ball-and-stick) with bonds colored according to the subunit;
Lys246 makes Schiff base to atom C4 of the inhibitor. The 4-OSA
molecules are shown (ball-and-stick) with bonds in green. Atom
color code is C, green; N, blue; O, red.
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Figure 6.
Fig. 6. Schematic diagram of the hydrogen bonding of
4-OSA (A) and 4,7-DOSA (B) with E. coli PBGS. The carbon atoms
of 4-OSA and 4,7-DOSA are numbered. Water molecules are
represented by single oxygen atoms as O. Dashed lines indicate
potential hydrogen bonds using a heteroatom distance of  3.2 Å.
Hydrogen bonds are depicted for subunits A. In subunit B the
Gly213(O)-Arg204(N), the 4-OSA(O)-Arg204(NE), and the
4-OSA(O)-water(connected to Gln219) distances are 3.5-3.8
Å. Dotted lines indicate the Zn2+ ligand bonds, which are
each ~2.4 Å.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2002,
277,
19792-19799)
copyright 2002.
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Secondary reference #1
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Title
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Mechanistic basis for suicide inactivation of porphobilinogen synthase by 4,7-Dioxosebacic acid, An inhibitor that shows dramatic species selectivity.
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Authors
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J.Kervinen,
E.K.Jaffe,
F.Stauffer,
R.Neier,
A.Wlodawer,
A.Zdanov.
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Ref.
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Biochemistry, 2001,
40,
8227-8236.
[DOI no: ]
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PubMed id
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