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  • In order to consolidate our genetic funding we performed sev


    In order to consolidate our genetic funding, we performed several in silico analysis regarding the p.R85W mutation. The high conservation of R85 residue in all species suggests that it has an important role in glucokinase function. Pathogenic effect of the p.R85W is supported by in silico predictions that assess it to affect GCK structure and stability, altering thereby its function and therefore to be disease causing. Structural modeling gave further evidence for the pathogenicity of the p.R85W mutation. R85 is located in the β2 sheet, near a loop structure (L79- N83) implicated in active site of the enzyme (Petit et al., 2011). In the 1V4S conformation, interactions between R85 and residues E443 and S445 are abolished when R85 is substituted by a tryptophan. Moreover, W85 establishes two hydrogen bonds with D78 and one pi–Alkyl interactions with residue M107 destabilizing thereby the active site.
    Conflict of interest
    Introduction Glucokinase was one of rate-limiting enzymes of glycolysis. It mainly expressed in hepatocytes and beta cells of islets. It had “one-two punch’ effect on regulating blood glucose level in vivo (Couzin, 2003). In hepatocytes, it promoted glucose phosphorylation and subsequent pyruvate production, which could enter mitochondrial and take part in the tricarboxylic BLZ945 cycle under the aerobic condition, or transform into lactic acid reversibly in cytoplasm under anoxic condition. All above these could advance glucose disposition. In beta cells, when glucose was up-took by glucose transporter 2 and entered into the cytoplasm, glucokinase, as glucose sensor, promoted glucose metabolism and increased ATP/ADP ratio, then regulated glucose-stimulated insulin secretion. Otherwise, insulin could up-regulate glucokinase gene transcription and amplify its activity in both hepatocytes and beta cells furthermore (Hansmannel et al., 2006). Mutations in human glucokinase gene would result in glucokinase activity disorder, which could induce hyperglycemia such as permanent neonatal diabetes and maturity onset diabetes of young (Gloyn, 2003, Gloyn et al., 2005, Gasperikova et al., 2009), or persistent hyperinsulinemia hypoglycemia of infancy (Gloyn et al., 2003, Cuesta-Munoz et al., 2004, Sayed et al., 2009). Glucokinase over-expression in liver could also accelerate hepatic lipogenesis and circulating lipids (Ferre et al., 2003). Since the first glucokinase activator was reported in 2003 (Grimsby et al., 2003), there were many glucokinase activators found (Meininger et al., 2011, Sarabu et al., 2012, Kiyosue et al., 2013, Erion et al., 2014, Katz et al., 2016). Until now, although some of them had been entered into clinical research, there still was no compound labeled as anti-diabetes drug and used to treat diabetes in clinic. Among them, some had obvious adverse effects, such as hypoglycemia (Meininger et al., 2011, Amin et al., 2015, Katz et al., 2016, Zhi and Zhai, 2016), hypertriglyceridaemia (Katz et al., 2016) and fatty liver (De Ceuninck et al., 2013a, De Ceuninck et al., 2013b) or hepatic steatosis (De Ceuninck et al., 2013a, De Ceuninck et al., 2013b) and so on. So discovering potent glucokinase activator as drug of diabetes treatment without adverse effects was still the strategy of researchers. SHP289-04, as a potent glucokinase activator which was found by our lab, not only had the potential effect of anti-diabetes, but also ameliorated the fatty liver in spontaneous type 2 diabetes animal model KKAy mice.
    Material and methods
    Discussion Glucokinase was main glucose sensor in both hepatocytes and pancreatic beta cells. Activating glucokinase activity could down-regulate blood glucose level via promoting glucose metabolism in liver and glucose-stimulated insulin secretion in pancreas. The compound SHP289-04 reported in this paper was a potent glucokinase activator with suitable pharmacokinetics. It could influence the blood glucose-controlling effectively like the other glucokinase activators (Grimsby et al., 2003, McKerrecher et al., 2005). We also predicted the binding mode for SHP289-04 (Supplemental Fig. S1B) in the ligand-binding domains of glucokinase by using the CDOCKER docking program. SHP289-04 binds with Arg63 at the allosteric site of glucokinase similar to that of other reported complexes. Hydrogen bond network was formed between the Arg63 of glucokinase and amidine group of SHP289-04, which was important for the activity of glucokinase. This predicted binding mode would provide helpful information to further perform SAR study.