Synthesis of Bisubstrate Inhibitors of Porphobilinogen Synthase from <i>Pseudomonas aeruginosa</i>

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 <b>1</b> (ALA). Symmetrically linked dimers <b>7-11</b> derived from levulinic acid <b>3</b> (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 <i>IC</i>₅₀ and <i>K</i>_i values using PBGS from <i>Pseudomonas aeruginosa</i>. The polarity and the size of the functional group linking the two levulinic acid <b>3</b> units have a strong influence on the inhibition behavior.