Transition state analogues in quorum sensing and SAM recycling.

Vern L. Schramm, Jemy A. Gutierrez, Grace Cordovano, Indranil Basu, Chandan Guha, Thomas J. Belbin, Gary B. Evans, Peter C. Tyler, Richard H. Furneaux

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)75-76
Number of pages2
JournalNucleic acids symposium series (2004)
Issue number52
StatePublished - 2008

Fingerprint

Quorum Sensing
S-Adenosylmethionine
Recycling
Vibrio cholerae
Polyamines
Enzyme Inhibitors
DNA Methylation
Static Electricity
Isotopes
Antineoplastic Agents
Anti-Bacterial Agents
Gene Expression
Enzymes
Growth
5'-methylthioadenosine phosphorylase
Neoplasms
4'-deaza-1'-aza-2'-deoxy-1'-(9-methylene)-immucillin A

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Schramm, V. L., Gutierrez, J. A., Cordovano, G., Basu, I., Guha, C., Belbin, T. J., ... Furneaux, R. H. (2008). Transition state analogues in quorum sensing and SAM recycling. Nucleic acids symposium series (2004), (52), 75-76.

Transition state analogues in quorum sensing and SAM recycling. / Schramm, Vern L.; Gutierrez, Jemy A.; Cordovano, Grace; Basu, Indranil; Guha, Chandan; Belbin, Thomas J.; Evans, Gary B.; Tyler, Peter C.; Furneaux, Richard H.

In: Nucleic acids symposium series (2004), No. 52, 2008, p. 75-76.

Research output: Contribution to journalArticle

Schramm, VL, Gutierrez, JA, Cordovano, G, Basu, I, Guha, C, Belbin, TJ, Evans, GB, Tyler, PC & Furneaux, RH 2008, 'Transition state analogues in quorum sensing and SAM recycling.', Nucleic acids symposium series (2004), no. 52, pp. 75-76.
Schramm, Vern L. ; Gutierrez, Jemy A. ; Cordovano, Grace ; Basu, Indranil ; Guha, Chandan ; Belbin, Thomas J. ; Evans, Gary B. ; Tyler, Peter C. ; Furneaux, Richard H. / Transition state analogues in quorum sensing and SAM recycling. In: Nucleic acids symposium series (2004). 2008 ; No. 52. pp. 75-76.
@article{b47810c457ee4c089e1d40e1d12d824e,
title = "Transition state analogues in quorum sensing and SAM recycling.",
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 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.",
author = "Schramm, {Vern L.} and Gutierrez, {Jemy A.} and Grace Cordovano and Indranil Basu and Chandan Guha and Belbin, {Thomas J.} and Evans, {Gary B.} and Tyler, {Peter C.} and Furneaux, {Richard H.}",
year = "2008",
language = "English (US)",
pages = "75--76",
journal = "Nucleic acids symposium series (2004)",
issn = "1746-8272",
publisher = "Oxford University Press",
number = "52",

}

TY - JOUR

T1 - Transition state analogues in quorum sensing and SAM recycling.

AU - Schramm, Vern L.

AU - Gutierrez, Jemy A.

AU - Cordovano, Grace

AU - Basu, Indranil

AU - Guha, Chandan

AU - Belbin, Thomas J.

AU - Evans, Gary B.

AU - Tyler, Peter C.

AU - Furneaux, Richard H.

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78649410813&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649410813&partnerID=8YFLogxK

M3 - Article

C2 - 18776260

AN - SCOPUS:78649410813

SP - 75

EP - 76

JO - Nucleic acids symposium series (2004)

JF - Nucleic acids symposium series (2004)

SN - 1746-8272

IS - 52

ER -