Synthesis of bisubstrate inhibitors of porphobilinogen synthase from Pseudomonas aeruginosa.
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 (gamma-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 IC(50) and K(i) 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.
Gacond
Sabine
S
Institute of Chemistry, University of Neuchâtel, Neuchâtel, Switzerland.
Frère
Frederic
F
Nentwich
Merle
M
Faurite
Jean-Philippe
JP
Frankenberg-Dinkel
Nicole
N
Neier
Reinhard
R
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors*; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D000623:Porphobilinogen Synthase