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 K(I)(*) value of 0.43 microM.
Wnuk
Stanislaw F
SF
Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA. wnuk@fiu.edu
Robert
Jenay
J
Sobczak
Adam J
AJ
Meyers
Brandon P
BP
Malladi
Venkata L A
VL
Zhu
Jinge
J
Gopishetty
Bhaskar
B
Pei
Dehua
D
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013437:Carbon-Sulfur Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012266:Ribose / Q000737:chemistry; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C487472:S-ribosyl-L-homocysteine; D006710:Homocysteine; D012266:Ribose; D013437:Carbon-Sulfur Lyases; C117753:LuxS protein, Bacteria
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