PHENYLGLUCOSIDES AND THE NA+ GLUCOSE COTRANSPORTER (SGLT1) - ANALYSISOF INTERACTIONS/

Phenylglucosides are transported by the intestinal Na+/glucose cotrans porter (SGLT1) and phlorizin, the classical competitive inhibitor of S GLT1, is also a phenylglucoside. To investigate the structural require ments for binding of substrates to SGLT1, we have studied the interact ions between phenylglucosides and the cotransporter expressed in Xenop us oocytes using tracer uptake and electrophysiological methods. Some phenylglucosides inhibited the Na+-dependent uptake of C-14-alpha-meth yl-D-glucopyranoside (alpha MDG) with apparent K(i)s in the range 0.1 to 20 mM, while others had no effect. Electrophysiological experiments indicated that phenylglucosides can act either as: (1) transported su bstrates, e.g., arbutin; (2) nontransported inhibitors, e.g., glucosyl phenyl-isothiocyanate; or (3) noninteracting sugars, e.g., salicin. Th e transported substrates (glucose, arbutin, phenylglucoside and helici n) induced different maximal currents, and computer simulations showed that this may be explained by a difference in the translocation rates of the sugar and Na+-loaded transporter. Computational chemistry indi cated that all these beta-phenylglucosides have similar 3-D structures . Analysis showed that among the side chains in the para position of t he phenyl ring the -OH group (arbutin) facilitates transport, but the -NCS (glucosylphenyl-isothiocyanate) inhibits transport. In the ortho position, -CH2OH (salicin) prevents interaction, but the aldehyde (hel icin) permits the molecule to be transported. Studies such as these ma y help to understand the geometry and nature of glucoside binding to S GLT1.