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First published on November 16, 2006; DOI: 10.1124/mol.106.030288

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Received for publication August 28, 2006.
Revised October 23, 2006.
Accepted for publication November 15, 2006.

Imino Sugars are Potent Agonists of the Human Glucose Sensor SGLT3

Andrew A. Voss 1*, Ana A. Diez-Sampedro 1, Bruce A. Hirayama 1, Donald D.F. Loo 1, Ernest M. Wright 1

1 David Geffen School of Medicine at UCLA

* Address correspondence to: E-mail: avoss{at}mednet.ucla.edu

Abstract

Imino sugars are used to treat type 2 diabetes mellitus (Glyset®; miglitol) and lysosomal storage disorders (Zavesca®; miglustat) based on the inhibition of {alpha}-glucosidases and glucosyltranferases. In this substrate specificity study, we examined the interactions of imino sugars with a novel human glucose sensor, sodium/glucose cotransporter type 3 (hSGLT3), using expression in Xenopus laevis oocytes and electrophysiology. The results for hSGLT3 are compared to those for {alpha}-glucosidases and human SGLT type 1 (hSGLT1), a well-characterized sodium/glucose cotransporter of the SGLT gene family. Generally, substrates have lower apparent affinities (K0.5) for hSGLT3 than hSGLT1 (D-glucose, {alpha}-methyl-D-glucose, 1-deoxy-D-glucose, and 4-deoxy-4-fluoro-D-glucose exhibit K0.5 values of 19, 21, 43 and 17 mM for hSGLT3; and 0.5, 0.7, 10 and 0.07 mM for hSGLT1). However, specificity of hSGLT3 binding is greater (D-galactose and 4-deoxy-4-fluoro-D-galactose are not hSGLT3 substrates, but have hSGLT1 K0.5 values of 0.6 and 1.3 mM). An important deviation from this trend is potent hSGLT3 activation by the imino sugars 1-deoxynojirimycin (DNJ), N-hydroxylethyl-1-deoxynojirimycin (miglitol), N-butyl-1-deoxynojirimycin (miglustat), N-ethyl-1-deoxynojirimycin and 1-deoxynojirimycin-1-sulfonic acid, with K0.5 values of 0.5 - 9 microM. The diastereomer 1-deoxygalactonojirimycin activates hSGT3 with a K0.5 value of 11 mM, a 3000-fold less potent interaction than is observed for DNJ (4 microM). These imino sugar binding characteristics are similar to those for {alpha}-glucosidases, but there are no interactions with hSGLT1. This work provides insights into hSGLT3 & 1 substrate binding interactions, establishes a pharmacological profile to study endogenous hSGLT3, and may have important ramifications for the clinical application of imino sugars.


Key words: Ion transporters (SERCA, Na/K ATPase, CFTR), Sugars, Structure-activity relationships and modeling, Func. analysis receptor/ion channel mutants


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