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Title: Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A

Abstract

S-Adenosyl-L-methionine (SAM) is an enzyme cofactor used in methyl transfer reactions and polyamine biosynthesis. The biosynthesis of SAM from ATP and L-methionine is performed by the methionine adenosyltransferase enzyme family (Mat; EC 2.5.1.6). Human methionine adenosyltransferase 2A (Mat2A), the extrahepatic isoform, is often deregulated in cancer. We identified a Mat2A inhibitor, PF-9366, that binds an allosteric site on Mat2A that overlaps with the binding site for the Mat2A regulator, Mat2B. Studies exploiting PF-9366 suggested a general mode of Mat2A allosteric regulation. Allosteric binding of PF-9366 or Mat2B altered the Mat2A active site, resulting in increased substrate affinity and decreased enzyme turnover. These data support a model whereby Mat2B functions as an inhibitor of Mat2A activity when methionine or SAM levels are high, yet functions as an activator of Mat2A when methionine or SAM levels are low. The ramification of Mat2A activity modulation in cancer cells is also described.

Authors:
ORCiD logo; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1405006
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Chemical Biology; Journal Volume: 13; Journal Issue: 7
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Quinlan, Casey L., Kaiser, Stephen E., Bolaños, Ben, Nowlin, Dawn, Grantner, Rita, Karlicek-Bryant, Shannon, Feng, Jun Li, Jenkinson, Stephen, Freeman-Cook, Kevin, Dann, Stephen G., Wang, Xiaoli, Wells, Peter A., Fantin, Valeria R., Stewart, Al E., and Grant, Stephan K. Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. United States: N. p., 2017. Web. doi:10.1038/nchembio.2384.
Quinlan, Casey L., Kaiser, Stephen E., Bolaños, Ben, Nowlin, Dawn, Grantner, Rita, Karlicek-Bryant, Shannon, Feng, Jun Li, Jenkinson, Stephen, Freeman-Cook, Kevin, Dann, Stephen G., Wang, Xiaoli, Wells, Peter A., Fantin, Valeria R., Stewart, Al E., & Grant, Stephan K. Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. United States. doi:10.1038/nchembio.2384.
Quinlan, Casey L., Kaiser, Stephen E., Bolaños, Ben, Nowlin, Dawn, Grantner, Rita, Karlicek-Bryant, Shannon, Feng, Jun Li, Jenkinson, Stephen, Freeman-Cook, Kevin, Dann, Stephen G., Wang, Xiaoli, Wells, Peter A., Fantin, Valeria R., Stewart, Al E., and Grant, Stephan K. 2017. "Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A". United States. doi:10.1038/nchembio.2384.
@article{osti_1405006,
title = {Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A},
author = {Quinlan, Casey L. and Kaiser, Stephen E. and Bolaños, Ben and Nowlin, Dawn and Grantner, Rita and Karlicek-Bryant, Shannon and Feng, Jun Li and Jenkinson, Stephen and Freeman-Cook, Kevin and Dann, Stephen G. and Wang, Xiaoli and Wells, Peter A. and Fantin, Valeria R. and Stewart, Al E. and Grant, Stephan K.},
abstractNote = {S-Adenosyl-L-methionine (SAM) is an enzyme cofactor used in methyl transfer reactions and polyamine biosynthesis. The biosynthesis of SAM from ATP and L-methionine is performed by the methionine adenosyltransferase enzyme family (Mat; EC 2.5.1.6). Human methionine adenosyltransferase 2A (Mat2A), the extrahepatic isoform, is often deregulated in cancer. We identified a Mat2A inhibitor, PF-9366, that binds an allosteric site on Mat2A that overlaps with the binding site for the Mat2A regulator, Mat2B. Studies exploiting PF-9366 suggested a general mode of Mat2A allosteric regulation. Allosteric binding of PF-9366 or Mat2B altered the Mat2A active site, resulting in increased substrate affinity and decreased enzyme turnover. These data support a model whereby Mat2B functions as an inhibitor of Mat2A activity when methionine or SAM levels are high, yet functions as an activator of Mat2A when methionine or SAM levels are low. The ramification of Mat2A activity modulation in cancer cells is also described.},
doi = {10.1038/nchembio.2384},
journal = {Nature Chemical Biology},
number = 7,
volume = 13,
place = {United States},
year = 2017,
month = 5
}
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