© 2008 Oxford University Press
This article appears in the following Nucleic Acid Symposium Series issue: Joint Symposium of the 18th International Roundtable on Nucleosides, Nucleotides and Nucleic Acids and the 35th International Symposium on Nucleic Acids Chemistry [View the issue table of contents]
Transition state analogues in quorum sensing and SAM recycling
1Albert Einstein College of Medicine, Bronx, New York, 10805, USA and 2Industrial Research Ltd., Lower Hutt, New Zealand
*Corresponding Author. E-mail: vern{at}aecom.yu.edu
Abstract
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 Sadenosylmethionine (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.