Glycoside binding and translocation in Na+-dependent glucose cotransporters: Comparison of SGLT1 and SGLT3

Using cotransporters as drug delivery vehicles is a topic of continuing int erest, We examined glucose derivatives containing conjugated aromatic rings using two isoforms of the Na+/glucose cotransporter: human SGLT1 (hSGLT1) and pig SGLT3 (pSGLT3, SAAT1). Our studies indicate that there is similarit y between SGLT1 and SGLT3 in the overall architecture of the vestibule lead ing to the sugar-binding site but differences in translocation pathway inte ractions. Indican was transported by hSGLT1 with higher affinity (K-0.5, 0. 06 mM) and 2-naphthylglucose with lower affinity (K-0.5 mM) than alpha-meth yl-D-glucopyranoside (alpha MDG 0.2 mM). Both were poorly transported (maxi mal velocities, I-max, 14% and 8% of alpha MDG). Other compounds were inhib itors (K(i)s 1-13 mM). In pSGLT3, indican and 2-naphthylglucose were transp orted with higher affinity than alpha MDG (K(0.5)s 0.9, 0.2 and 2.5 mM and relative I(max)s of 80, 25 and 100%). Phenylglucose and arbutin were transp orted with higher I(max)s (130 and 120%) and comparable K(0.5)s (8 and 1 mM ). Increased affinity of indican relative to alpha MDG suggests that nitrog en in the pyrrole ring is favorable in both transporters. Higher affinity o f 2-naphthylglucose for pSGLT3 than hSGLT1 suggests more extensive hydropho bic/aromatic interaction in pSGLT3 than in hSGLT1, Our results indicate tha t bulky hydrophobic glucosides can be transported by hSGLT1 and pSGLT3, and discrimination between them is based on steric factors and requirements fo r H-bonding. This provides information for design of glycosides with potent ial therapeutic value.