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Mechanistic and structural requirements for active site labeling of phosphoglycerate mutase by spiroepoxides

Academic Article
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Overview

related to degree

  • Evans, Michael, Ph.D. in Chemistry, Scripps Research 2001 - 2007

authors

  • Evans, Michael
  • Morris, G. M.
  • Wu, J.
  • Olson, Arthur
  • Sorensen, Erik J.
  • Cravatt, Benjamin

publication date

  • 2007

journal

  • Molecular Biosystems  Journal

abstract

  • We recently reported the pharmacological screening of a natural products-inspired library of spiroepoxide probes, resulting in the discovery of an agent MJE3 that displayed anti-proliferative effects in human breast cancer cells. MJE3 was found to covalently inactivate phosphoglycerate mutase-1 (PGAM1), a glycolytic enzyme with postulated roles in cancer cell metabolism and proliferation. Considering that MJE3 is one of the first examples of a cell-permeable, small-molecule inhibitor for PGAM1, we pursued a detailed examination of its mechanism and structural requirements for covalent inactivation. MJE3 was found to label PGAM1 on lysine-100, a conserved active site residue implicated in substrate recognition. Structural features of MJE3 important for PGAM1 labeling included two key recognition elements (an indole ring and carboxylic acid), the stereochemical orientation of the spiroepoxide, and presentation of these various binding/reactive groups on a rigid cyclohexane scaffold. Modeling studies of the docked MJE3-PGAM1 complex provide a structural rationale for these stringent requirements. Overall, these studies indicate that a special combination of binding and reactive elements are united in the MJE3 structure to inactivate PGAM1. More generally, our findings provide further evidence that useful pharmacological tools can emerge from screening structurally diverse libraries of protein-reactive probes.

subject areas

  • Animals
  • Binding Sites
  • Blotting, Western
  • COS Cells
  • Cell Line, Tumor
  • Cell Proliferation
  • Cercopithecus aethiops
  • Epoxy Compounds
  • Humans
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Phosphoglycerate Mutase
  • Protein Binding
  • Protein Structure, Secondary
  • Structure-Activity Relationship
  • Transfection
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Identity

International Standard Serial Number (ISSN)

  • 1742-206X

Digital Object Identifier (DOI)

  • 10.1039/b705113a

PubMed ID

  • 17579775
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Additional Document Info

start page

  • 495

end page

  • 506

volume

  • 3

issue

  • 7

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