Transition state analogues in quorum sensing and SAM recycling.
Transition state structures can be derived from kinetic isotope effects and computational chemistry. Molecular electrostatic potential maps of transition states serve as blueprints to guide synthesis of transition state analogue inhibitors of target enzymes. 5'- Methylthioadenosine phosphorylase (MTAP) functions in the polyamine pathway by recycling methylthioadenosine (MTA) and maintaining cellular S-adenosylmethionine (SAM). Its transition state structure was used to guide synthesis of MT-DADMe-ImmA, a picomolar inhibitor that shows anticancer effects against solid tumors. Biochemical and genomic analysis suggests that MTAP inhibition acts by altered DNA methylation and gene expression patterns. A related bacterial enzyme, 5'-methylthioadenosine nucleosidase (MTAN), functions in pathways of quorum sensing involving AI-1 and AI-2 molecules. Transition states have been solved for several bacterial MTANs and used to guide synthesis of powerful inhibitors with dissociation constants in the femtomolar to picomolar range. BuT-DADMe-ImmA blocks quorum sensing in Vibrio cholerae without changing bacterial growth rates. Transition state analogue inhibitors show promise as anticancer and antibacterial agents.
Schramm
Vern L
VL
Albert Einstein College of Medicine, Bronx, New York, NY 10805, USA. vern@aecom.yu.edu
Gutierrez
Jemy A
JA
Cordovano
Grace
G
Basu
Indranil
I
Guha
Chandan
C
Belbin
Thomas J
TJ
Evans
Gary B
GB
Tyler
Peter C
PC
Furneaux
Richard H
RH
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D053038:Quorum Sensing / Q000187:drug effects*; D012436:S-Adenosylmethionine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D012436:S-Adenosylmethionine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D009699:N-Glycosyl Hydrolases; D000225:Adenine
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