Phenylglucosides and the Na+/glucose cotransporter (SGLT1): analysis of interactions.
Phenylglucosides are transported by the intestinal Na+/glucose cotransporter (SGLT1) and phlorizin, the classical competitive inhibitor of SGLT1, is also a phenylglucoside. To investigate the structural requirements for binding of substrates to SGLT1, we have studied the interactions between phenylglucosides and the cotransporter expressed in Xenopus oocytes using tracer uptake and electrophysiological methods. Some phenylglucosides inhibited the Na(+)-dependent uptake of 14C-alpha-methyl-D-glucopyranoside (alpha MDG) with apparent Kis in the range 0.1 to 20 mM, while others had no effect. Electrophysiological experiments indicated that phenylglucosides can act either as: (1) transported substrates, e.g., arbutin; (2) nontransported inhibitors, e.g., glucosylphenyl-isothiocyanate; or (3) noninteracting sugars, e.g., salicin. The transported substrates (glucose, arbutin, phenylglucoside and helicin) 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 indicated that all these beta-phenylglucosides have similar 3-D structures. Analysis showed that among the side chains in the para position of the 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 (helicin) permits the molecule to be transported. Studies such as these may help to understand the geometry and nature of glucoside binding to SGLT1.
Lostao
M P
MP
Department of Physiology, UCLA School of Medicine 90024-1751.
Hirayama
B A
BA
Loo
D D
DD
Wright
E M
EM
D000818:Animals; D001104:Arbutin / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001692:Biological Transport / Q000502:physiology; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism* / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D004594:Electrophysiology; D005260:Female; D005947:Glucose / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D005960:Glucosides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000648:ultrastructure; D008562:Membrane Glycoproteins; D008564:Membrane Potentials / Q000502:physiology; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism* / Q000502:physiology*; D008757:Methylglucosides / Q000378:metabolism; D008871:Microvilli / Q000378:metabolism; D009004:Monosaccharide Transport Proteins; D009865:Oocytes / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D010695:Phlorhizin / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D011817:Rabbits; D051269:Sodium-Glucose Transporter 1; D014982:Xenopus laevis
D002352:Carrier Proteins; D005960:Glucosides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008757:Methylglucosides; D009004:Monosaccharide Transport Proteins; D051269:Sodium-Glucose Transporter 1; C027020:methylglucoside; D001104:Arbutin; D010695:Phlorhizin; D005947:Glucose