Discovery and evaluation of novel benzazepinone derivatives as glycogen phosphorylase inhibitors with potent activity

Glycogen phosphorylase (GP) is a key enzyme of glycogen catabolism, so it is significant to discover a new GP inhibitor. A series of benzazepinone derivatives were discovered as GP inhibitors with potent activity. Among these derivatives, compound 5d showed significant potential against rabbit muscle GPa (IC50 = 0.25 ± 0.05 μM) and cellular efficacy. The in vivo study revealed that 5d significantly inhibited increases in fasting blood glucose level in two kinds of hyperglycemic mice models. The possible binding mode of compound 5d was explored based on molecular docking simulations. These results indicated that derivatives with benzazepinone were potential chemical entities against hyperglycemia.

Acquisition of a type 3 secretion signal in an housekeeping enzyme shaped glycogen metabolism in Chlamydia

ABSTRACTThe obligate intracellular bacteria Chlamydia trachomatis store glycogen in the lumen of the vacuoles in which they grow. Glycogen catabolism generates glucose-1-phosphate (Glc1P), while the bacteria are capable of taking up only glucose-6-phosphate (Glc6P). We tested whether the conversion of Glc1P into Glc6P could be catalyzed by a phosphoglucomutase (PGM) of host or bacterial origin. We found no evidence for the presence of the host enzyme in the vacuole. In C. trachomatis, two proteins are potential PGMs. By reconstituting the reaction, and by complementing PGM deficient fibroblasts, we demonstrated that only CT295 displayed robust PGM activity. Furthermore, we showed that glycogen accumulation by a subset of Chlamydia species correlated with the presence of a type three secretion (T3S) signal in their PGM. In conclusion, we established that the conversion of Glc1P into Glc6P was accomplished by a bacterial PGM, through the acquisition of a T3S signal in a “housekeeping” gene.