2. Academic Validation
  3. Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A

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

  • Nat Chem Biol. 2017 Jul;13(7):785-792. doi: 10.1038/nchembio.2384.
Casey L Quinlan 1,  Stephen E Kaiser 2,  Ben Bolaños 2,  Dawn Nowlin 1,  Rita Grantner 1,  Shannon Karlicek-Bryant 1,  Jun Li Feng 2,  Stephen Jenkinson 3,  Kevin Freeman-Cook 2,  Stephen G Dann 1,  Xiaoli Wang 1,  Peter A Wells 1,  Valeria R Fantin 4,  Al E Stewart 2,  Stephan K Grant 1
Affiliations

Affiliations

  • 1 Oncology Research and Development, Pfizer Inc., San Diego, California, USA.
  • 2 Oncology Medicinal Chemistry, Pfizer Inc., San Diego, California, USA.
  • 3 Drug Safety and Pharmacology, Pfizer Inc., San Diego, California, USA.
  • 4 ORIC Pharmaceuticals, South San Francisco, California, USA.
PMID: 28553945 DOI: 10.1038/nchembio.2384
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.

Figures
Products