Faculté des sciences

Synthesis of Bisubstrate Inhibitors of Porphobilinogen Synthase from Pseudomonas aeruginosa

Gacond, Sabine ; Frère, Frederic ; Nentwich, Merle ; Faurite, Jean-Philippe ; Frankenberg-Dinkel, Nicole ; Neier, Reinhard

In: Chemistry & Biodiversity, 2007, vol. 4, no. 2, p. 189-202

Porphobilinogen synthase (PBGS) synthesizes porphobilinogen 2 (PBG), the common precursor of all natural tetrapyrroles, through an asymmetric condensation of two molecules of 5-aminolevulinic acid 1 (ALA). Symmetrically linked dimers 7-11 derived from levulinic acid 3 (γ-oxovaleric acid) have been synthesized to mimic the assumed bisubstrate bound to the active site of... Plus

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    Summary
    Porphobilinogen synthase (PBGS) synthesizes porphobilinogen 2 (PBG), the common precursor of all natural tetrapyrroles, through an asymmetric condensation of two molecules of 5-aminolevulinic acid 1 (ALA). Symmetrically linked dimers 7-11 derived from levulinic acid 3 (γ-oxovaleric acid) have been synthesized to mimic the assumed bisubstrate bound to the active site of the enzyme. Their inhibition potential was characterized by determination of the IC50 and Ki values using PBGS from Pseudomonas aeruginosa. The polarity and the size of the functional group linking the two levulinic acid 3 units have a strong influence on the inhibition behavior.