Understanding the Rate-Limiting Step of Glycogenolysis by Using QM/MM Calculations on Human Glycogen Phosphorylase

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Natercia F Bras (Author) FCUP; Pedro A Fernandes (Author) FCUP; Ramos, MJ (Author) FCUP

Journal

Title: ChemMedChem

Vol. 13

Pages: 1608-1616

ISSN: 1860-7179

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 5 Citations

Scopus - 5 Citations

Other information

Authenticus ID: P-00P-G0V

DOI: 10.1002/cmdc.201800218

Abstract (EN): Liver glycogen phosphorylase (GP) is a key enzyme for human health, as its increased activity is associated with type2 diabetes. The GP catalytic mechanism has been explored by quantum mechanics/molecular mechanics (QM/MM) methods. Herein, we propose a mechanism that proceeds by three steps: 1)it begins with transfer of a hydrogen atom from the phosphate group of the pyridoxal 5-phosphate (HPO42--PLP) cofactor to the phosphate substrate; 2)the glycosidic linkage is then cleaved through protonation of the glycosidic oxygen atom by a hydroxy group of the inorganic phosphate group; and 3)an oxygen atom of the phosphate performs a nucleophilic attack on the anomeric carbon atom of glucose, concomitant with the return of a proton from phosphate to PO43--PLP, which finally leads to formation of the glucose-1-phosphate product and recovers the initial state of the PLP cofactor. The glycosidic bond cleavage and nucleophilic attack from the phosphate group to the glycosyl molecule have the highest activation free energies. The structural properties of the hereby characterized transition states could be very useful in structure-based drug design studies against liver GP.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9