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Imino sugars potently activate the human glucose senor SGLT3
Author(s) -
Voss Andrew Alvin,
DiezSampedro Ana,
Hirayama Bruce A.,
Loo Donald D.F.,
Wright Ernest M.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a530-a
Subject(s) - chemistry , xenopus , cotransporter , binding site , binding affinities , biochemistry , galactose , sugar , glucosidases , stereochemistry , sodium , enzyme , receptor , organic chemistry , gene
This study examines the pharmacology and binding site structure of the novel human glucose sensor, sodium/glucose cotransporter type 3 (hSGLT3). We used electrophysiology and expression in Xenopus laevis oocytes, the results are compared to hSGLT1 and α‐glucosidases. Generally, hSGLT3 exhibits lower apparent affinities (K 0.5 ) but greater specificity for substrates than hSGLT1 (hSGLT3 K 0.5 values for D‐glucose analogs are 19 – 43 mM, and those for hSGLT1 = 0.07 – 10 mM; however, D‐galactose is not a hSGLT3 substrate, but is transported by hSGLT1 with the same K 0.5 as glucose). An important deviation from this trend is potent hSGLT3 activation by imino sugars (K 0.5 = 0.5 – 5 microM), including 1‐deoxynojirimycin (DNJ), N‐hydroxylethyl‐1‐deoxynojirimycin (Glyset®; miglitol) and N‐butyl‐1‐deoxynojirimycin (Zavesca®; miglustat). The diastereomer 1‐deoxygalactonojirimycin activates hSGT3 with a K 0.5 = 11 mM, (3000‐fold less potent than DNJ). For hSGLT1, no interaction with these imino sugars is observed. α‐Glucosidases exhibit similar imino sugar and glucose binding characteristics as hSGLT3, suggesting similar binding sites. Hence, crystal structures of DNJ‐glucosidase complexes provide insights into the hSGLT3 binding site architecture. This work also establishes a pharmacological profile to study endogenous hSGLT3 and may have important ramifications for the clinical application of imino sugars. Supported by NIH grants DK072818 (A.A.V.), DK19567 and DK44602.