A New Potent Inhibitor of Glycogen Phosphorylase Reveals the Basicity of the Catalytic Site. Issue 37 (19th June 2017)

• Record Type: Journal Article
• Authors: Mamais, Michael; Degli Esposti, Alessandra; Kouloumoundra, Virginia; Gustavsson, Thomas; Monti, Filippo; Venturini, Alessandro; Chrysina, Evangelia D.; Markovitsi, Dimitra; Gimisis, Thanasis
• Is Part Of: Chemistry. Volume 23:Issue 37(2017)
• Page Start: 8800
• Page End: 8805
• Publication Date: 2017-06-19
• Subjects: acridone based inhibitors -- glycogen phosphorylase -- optical spectra -- quantum chemistry -- X-ray crystallography; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201701591
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: 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. Abstract : It's so basic : Glycogen phosphorylase (GP) is an enzyme that plays a key role in glucose regulation. The design and synthesis of a new potent inhibitor of GP is described. Exploiting its optical properties, it is shown that, due to an extended hydrogen‐bonding network, the local pH in the GP catalytic site is higher than 12.