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PDBsum entry 1i8j
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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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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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Abstract
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4,7-Dioxosebacic acid (4,7-DOSA) is an active site-directed irreversible
inhibitor of porphobilinogen synthase (PBGS). PBGS catalyzes the first common
step in the biosynthesis of the tetrapyrrole cofactors such as heme, vitamin
B(12), and chlorophyll. 4,7-DOSA was designed as an analogue of a proposed
reaction intermediate in the physiological PBGS-catalyzed condensation of two
molecules of 5-aminolevulinic acid. As shown here, 4,7-DOSA exhibits
time-dependent and dramatic species-specific inhibition of PBGS enzymes. IC(50)
values vary from 1 microM to 2.4 mM for human, Escherichia coli, Bradyrhizobium
japonicum, Pseudomonas aeruginosa, and pea enzymes. Those PBGS utilizing a
catalytic Zn(2+) are more sensitive to 4,7-DOSA than those that do not. Weak
inhibition of a human mutant PBGS establishes that the inactivation by 4,7-DOSA
requires formation of a Schiff base to a lysine that normally forms a Schiff
base intermediate to one substrate molecule. A 1.9 A resolution crystal
structure of E. coli PBGS complexed with 4,7-DOSA (PDB code ) shows one dimer
per asymmetric unit and reveals that the inhibitor forms two Schiff base
linkages with each monomer, one to the normal Schiff base-forming Lys-246 and
the other to a universally conserved "perturbing" Lys-194 (E. coli numbering).
This is the first structure to show inhibitor binding at the second of two
substrate-binding sites.
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