In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures.

Article Details

Citation

Kuriyama C, Kamiyama O, Ikeda K, Sanae F, Kato A, Adachi I, Imahori T, Takahata H, Okamoto T, Asano N

In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures.

Bioorg Med Chem. 2008 Aug 1;16(15):7330-6. doi: 10.1016/j.bmc.2008.06.026. Epub 2008 Jun 18.

PubMed ID
18595718 [ View in PubMed
]
Abstract

We investigated in vitro inhibition of mammalian carbohydrate-degrading enzymes by six-membered sugar mimics and their evaluation in cell cultures. 1-Deoxynojirimycin (DNJ) showed no significant inhibition toward glycogen phosphorylase (GP) but was a potent inhibitor of another glycogen-degrading enzyme, amylo-1,6-glucosidase (1,6-GL), with an IC(50) value of 0.16 microM. In primary rat hepatocytes, the inhibition of glycogen breakdown by DNJ reached plateau at 100 microM with 25% inhibition and then remained unchanged. The potent GP inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (D-AB1) inhibited hepatic glucose production with an IC(50) value of about 9 microM and the inhibition by D-AB1 was further enhanced in the presence of DNJ. DNJ and alpha-homonojirimycin (HNJ) are very potent inhibitors of rat intestinal maltase, with IC(50) values of 0.13 and 0.08 microM, respectively, and also showed a similar strong inhibition toward maltase in Caco-2 cell model system, with IC(50) value of 0.05 and 0.10 microM, respectively. D-Isofagomine (D-IFG) and L-IFG are competitive and noncompetitive inhibitors of human lysosomal beta-glucosidase (beta-GL), respectively, with K(i) values of 8.4 nM and 6.9 microM. D-IFG increased intracellular beta-GL activity by twofold at 10 microM in Gaucher N370S cell line as an 'active-site-specific' chaperone, and surprisingly a noncompetitive inhibitor L-IFG also increased intracellular beta-GL activity by 1.6-fold at 500 microM.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MiglitolLysosomal alpha-glucosidaseIC 50 (nM)350N/AN/ADetails
MiglitolLysosomal alpha-glucosidaseIC 50 (nM)1000N/AN/ADetails