Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system

Raja, Mobeen; Kinne, Rolf

doi:10.1016/j.biochi.2015.06.003

Cited by 21 publications

(28 citation statements)

References 42 publications

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“…Based on primary sequence analyses and computer modeling prediction, the increase in secondary structural contents (helices H1, H2 and H3) could promote high specificity and strong affinities of phlorizin and its analogs for SGLT2 as compared to SGLT1. 48 These assumptions fit quite nicely with the recently illustrated homology modeling and molecular dynamics simulation studies predicting higher stability of SGLT2 binding complexes than SGLT1, and an increase in hydrophobicity might also promote hydrogen bonding within the binding pocket upon inhibitor binding. 27 Furthermore, for SGLT2 an additional binding of the B ring of phlorizin to H3 is expected which could explain the high affinity of dapagliflozin, which has an extended CH 2 -CH 3 chain at C6 of the B ring.…”

Section: Interaction Of Phlorizin With Different Members Of the Sglt supporting

confidence: 75%

“…The regions between TMH 12 and 13 of the vSGLT transporter structure (PDB ID: 3DH4) were selected as templates for helices H1 and H2 (in green) as described in detail in ref. 48. Phlorizin (Pz) is shown in gray.…”

Section: Modeling the Binding Of Hexyl-glucoside To Subdomain IIImentioning

confidence: 99%

“…Interestingly, the sugar binding residues were also found to be quite conserved among these SGLT members, thereby indicating a common mechanism by which other SGLTs are inhibited by phlorizin or its high affinity analogs. 48 Structurally similar analogs of phlorizin, like dapagliflozin and canagliflozin, exhibit better absorption in the Fig. 13 Schematic representation of phlorizin interaction with subdomain III of various members of the SGLT family.…”

Section: Interaction Of Phlorizin With Different Members Of the Sglt mentioning

confidence: 99%

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The role of transporter ectodomains in drug recognition and binding: phlorizin and the sodium–glucose cotransporter

et al. 2016

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Section: Interaction Of Phlorizin With Different Members Of the Sglt supporting

confidence: 75%

Section: Modeling the Binding Of Hexyl-glucoside To Subdomain IIImentioning

confidence: 99%

Section: Interaction Of Phlorizin With Different Members Of the Sglt mentioning

confidence: 99%

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The role of transporter ectodomains in drug recognition and binding: phlorizin and the sodium–glucose cotransporter

et al. 2016

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“…To further confirm that the changes in Isc after glucose or 3-O-methyl glucose administration were mediated by SGLT-1 (or related family members), we performed separate experiments in which tissues were treated with phloridzin, which blocks SGLT1 and to lesser extent other SGLT1 isoforms [ 14 ]. In the case of intestinal tissues exposed to 3-O-methyl glucose, the solute-induced ΔIsc was almost completely inhibited by pre-treatment with phloridzin ( Fig 3B and 3C ).…”

Section: Resultsmentioning

confidence: 99%

Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy

et al. 2015

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Background and AimsMorbidity and mortality from acute diarrheal disease remains high, particularly in developing countries and in cases of natural or man-made disasters. Previous work has shown that the small molecule clotrimazole inhibits intestinal Cl- secretion by blocking both cyclic nucleotide- and Ca2+-gated K+ channels, implicating its use in the treatment of diarrhea of diverse etiologies. Clotrimazole, however, might also inhibit transporters that mediate the inwardly directed electrochemical potential for Na+-dependent solute absorption, which would undermine its clinical application. Here we test this possibility by examining the effects of clotrimazole on Na+-coupled glucose uptake.Materials and MethodsShort-circuit currents (Isc) following administration of glucose and secretagogues were studied in clotrimazole-treated jejunal sections of mouse intestine mounted in Ussing chambers.ResultsTreatment of small intestinal tissue with clotrimazole inhibited the Cl- secretory currents that resulted from challenge with the cAMP-agonist vasoactive intestinal peptide (VIP) or Ca2+-agonist carbachol in a dose-dependent fashion. A dose of 30 μM was effective in significantly reducing the Isc response to VIP and carbachol by 50% and 72%, respectively. At this dose, uptake of glucose was only marginally affected (decreased by 14%, p = 0.37). There was no measurable effect on SGLT1-mediated sugar transport, as uptake of SGLT1-restricted 3-O-methyl glucose was equivalent between clotrimazole-treated and untreated tissue (98% vs. 100%, p = 0.90).ConclusionTreatment of intestinal tissue with clotrimazole significantly reduced secretory responses caused by both cAMP- and Ca2+-dependent agonists as expected, but did not affect Na+-coupled glucose absorption. Clotrimazole could thus be used in conjunction with oral rehydration solution as a low-cost, auxiliary treatment of acute secretory diarrheas.

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“…Here, we propose to reveal a molecular mechanism useful for inhibition of bacterial nourishment uptake, based on plant-derived phlorizin molecules and their synthetic derivatives, as well as on a set of natural SGLT inhibitors. Phlorizin is known to be at least a 1000-fold weaker inhibitor for bacterial vSGLT than for human intestinal brush border SGLT1 [6], probably due to the absence in vSGLT of the supposed phlorizin binding domain [7]. Hence, there is a need to understand the molecular mechanism of Na + dependent galactose transport inhibition.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of vSGLT inhibition by gneyulin reveals antiseptic properties against multidrug-resistant gram-negative bacteria

et al. 2019

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Faced with the worldwide spread of multidrug-resistant (MDR) bacterial strains, together with a lack of any appropriate treatment, urgent steps to combat infectious diseases should be taken. Usually, bacterial components are studied to understand, by analogy, the functioning of human proteins. However, molecular data from bacteria gathered over the past decades provide a sound basis for the search for novel approaches in medical care. With this current work, we want to direct attention to inhibition of the vSGLT glucose transporter from Vibrio parahaemolyticus belonging to the sodium solute symporter (SSS) family, to block sugar transport into the bacterial cell and, as a consequence, to limit its growth. Potential bacteriostatic properties can be drawn from commercially available drugs developed for human diseases. This goal can also be reached with natural components from traditional herbal medicine. The presented data from the numerical analysis of 44 known inhibitors of sodium glucose symporters shed light on potential novel approaches in fighting Gram-negative multidrug-resistant microorganisms.

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Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system

Cited by 21 publications

References 42 publications

The role of transporter ectodomains in drug recognition and binding: phlorizin and the sodium–glucose cotransporter

The role of transporter ectodomains in drug recognition and binding: phlorizin and the sodium–glucose cotransporter

Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy

Molecular mechanism of vSGLT inhibition by gneyulin reveals antiseptic properties against multidrug-resistant gram-negative bacteria

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