Inhibition of S-ribosylhomocysteinase (LuxS) by substrate analogues modified at the ribosyl C-3 position

S-Ribosylhomocysteinase (LuxS) catalyzes the cleavage of the thioether bond of S  -ribosylhomocysteine (SRH) to produce homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD), which is the precursor of type 2 autoinducer for bacterial cell–cell communication. In this work, we have synthesized several SRH analogues modified at the ribose C3 position as potential inhibitors of LuxS. While removal or methylation of the C3–OH resulted in simple competitive inhibitors of moderate potency, inversion of the C3 stereochemistry or substitution of fluorine for C3–OH resulted in slow-binding inhibitors of improved potency. The most potent inhibitor showed a KI∗ value of 0.43 μM.

S-Ribosylhomocysteine analogues that lack an enolizable hydroxyl group at the carbon-3 position act as competitive inhibitors of the LuxS enzyme.Figure optionsDownload as PowerPoint slide