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A New Potent Inhibitor of Glycogen Phosphorylase Reveals the Basicity of the Catalytic Site
Author(s) -
Mamais Michael,
Degli Esposti Alessandra,
Kouloumoundra Virginia,
Gustavsson Thomas,
Monti Filippo,
Venturini Alessandro,
Chrysina Evangelia D.,
Markovitsi Dimitra,
Gimisis Thanasis
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201701591
Subject(s) - glycogen phosphorylase , chemistry , catalysis , glycogen , hydrogen bond , active site , absorption (acoustics) , enzyme , absorption spectroscopy , derivative (finance) , stereochemistry , crystallography , biochemistry , molecule , organic chemistry , materials science , physics , quantum mechanics , financial economics , economics , composite material
The design and synthesis of a glucose‐based acridone derivative (GLAC), a potent inhibitor of glycogen phosphorylase (GP) are described. GLAC is the first inhibitor of glycogen phosphorylase, the electronic absorption properties of which are clearly distinguishable from those of the enzyme. This allows probing subtle interactions in the catalytic site. The GLAC absorption spectra, associated with X‐ray crystallography and quantum chemistry calculations, reveal that part of the catalytic site of GP behaves as a highly basic environment in which GLAC exists as a bis‐anion. This is explained by water‐bridged hydrogen‐bonding interactions with specific catalytic site residues.