1i8j

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{{STRUCTURE_1i8j| PDB=1i8j | SCENE= }}
{{STRUCTURE_1i8j| PDB=1i8j | SCENE= }}
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'''CRYSTAL STRUCTURE OF PORPHOBILINOGEN SYNTHASE COMPLEXED WITH THE INHIBITOR 4,7-DIOXOSEBACIC ACID'''
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===CRYSTAL STRUCTURE OF PORPHOBILINOGEN SYNTHASE COMPLEXED WITH THE INHIBITOR 4,7-DIOXOSEBACIC ACID===
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==Overview==
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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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{{ABSTRACT_PUBMED_11444968}}
==About this Structure==
==About this Structure==
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[[Category: Magnesium]]
[[Category: Magnesium]]
[[Category: Zinc]]
[[Category: Zinc]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 10:35:01 2008''

Revision as of 07:35, 1 July 2008

Image:1i8j.png

Template:STRUCTURE 1i8j

CRYSTAL STRUCTURE OF PORPHOBILINOGEN SYNTHASE COMPLEXED WITH THE INHIBITOR 4,7-DIOXOSEBACIC ACID

Template:ABSTRACT PUBMED 11444968

About this Structure

1I8J is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.

Reference

Mechanistic basis for suicide inactivation of porphobilinogen synthase by 4,7-dioxosebacic acid, an inhibitor that shows dramatic species selectivity., Kervinen J, Jaffe EK, Stauffer F, Neier R, Wlodawer A, Zdanov A, Biochemistry. 2001 Jul 27;40(28):8227-36. PMID:11444968

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