Probing the Active Site of Pseudomonas aeruginosa Porphobilinogen Synthase Using Newly Developed Inhibitors
Porphobilinogen synthase catalyzes the first committed step of the tetrapyrrole biosynthesis pathway. In an aldol-like condensation, two molecules of 5-aminolevulinic acid (ALA) form the first pyrrole, porphobilinogen. Newly synthesized analogues of a reaction intermediate of porphobilinogen synthas...
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| Veröffentlicht in: | Biochemistry (Easton) 2006-07, Vol.45 (27), p.8243-8253 |
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| container_issue | 27 |
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| container_title | Biochemistry (Easton) |
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| creator | Frère, Frederic Nentwich, Merle Gacond, Sabine Heinz, Dirk W Neier, Reinhard Frankenberg-Dinkel, Nicole |
| description | Porphobilinogen synthase catalyzes the first committed step of the tetrapyrrole biosynthesis pathway. In an aldol-like condensation, two molecules of 5-aminolevulinic acid (ALA) form the first pyrrole, porphobilinogen. Newly synthesized analogues of a reaction intermediate of porphobilinogen synthase have been employed in studying the active site and the catalytic mechanism of this early enzyme of tetrapyrrole biosynthesis. This study combines structural and kinetic evaluation of the inhibition potency of these inhibitors. In addition, one of the determined protein structures provides for the first time structural evidence of a magnesium ion in the active site. From these results, we can corroborate an earlier postulated enzymatic mechanism that starts with formation of a C−C bond, linking C3 of the A-side ALA to C4 of the P-side ALA through an aldole addition. The obtained data are discussed with respect to the current literature. |
| doi_str_mv | 10.1021/bi052611f |
| format | Article |
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In an aldol-like condensation, two molecules of 5-aminolevulinic acid (ALA) form the first pyrrole, porphobilinogen. Newly synthesized analogues of a reaction intermediate of porphobilinogen synthase have been employed in studying the active site and the catalytic mechanism of this early enzyme of tetrapyrrole biosynthesis. This study combines structural and kinetic evaluation of the inhibition potency of these inhibitors. In addition, one of the determined protein structures provides for the first time structural evidence of a magnesium ion in the active site. From these results, we can corroborate an earlier postulated enzymatic mechanism that starts with formation of a C−C bond, linking C3 of the A-side ALA to C4 of the P-side ALA through an aldole addition. 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In an aldol-like condensation, two molecules of 5-aminolevulinic acid (ALA) form the first pyrrole, porphobilinogen. Newly synthesized analogues of a reaction intermediate of porphobilinogen synthase have been employed in studying the active site and the catalytic mechanism of this early enzyme of tetrapyrrole biosynthesis. This study combines structural and kinetic evaluation of the inhibition potency of these inhibitors. In addition, one of the determined protein structures provides for the first time structural evidence of a magnesium ion in the active site. From these results, we can corroborate an earlier postulated enzymatic mechanism that starts with formation of a C−C bond, linking C3 of the A-side ALA to C4 of the P-side ALA through an aldole addition. 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| subjects | Binding Sites Catalysis - drug effects Crystallography, X-Ray Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Kinetics Magnesium - chemistry Porphobilinogen Synthase - antagonists & inhibitors Porphobilinogen Synthase - chemistry Porphobilinogen Synthase - genetics Protein Conformation Pseudomonas aeruginosa Pseudomonas aeruginosa - enzymology Pseudomonas aeruginosa - genetics Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - chemistry Recombinant Proteins - genetics |
| title | Probing the Active Site of Pseudomonas aeruginosa Porphobilinogen Synthase Using Newly Developed Inhibitors |
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