Ab initio molecular electrostatic potentials of perillartine analogs: implications for sweet-taste receptor recognition

Ab initio computational studies have been carried out for three molecules that are commonly classed as antiaromatic: cyclobutadiene (1), 1,3-diazacyclobutadiene (7), and 1,4-dihydropyrazine (6). Their dinitro and diamino derivatives were also investigated. Stabilizing or destabilizing energetic effects were quantified by means of the isodesmic reaction procedure at the MP2/6-31G*//HF/3-21G level, and calculated molecular electrostatic potentials (HF/STO-5G//HF/3-21G) were used as a probe of electron delocalization. Our results do not show extensive delocalization in the π systems of any one of the three parent molecules. The destabilization found for 1 and 7 is attributed primarily to strain and to repulsion between the localized π electrons in the C=C and C=N bonds, respectively. However, 6 is significantly stabilized, presumably due to limited delocalization of the nitrogen lone pairs. NH2 groups are highly stabilizing, apparently because of lone pair delocalization. NO2 is neither uniformly stabilizing nor destabilizing.

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Crystal Structure of Thaumatin I, a Sweet Taste Receptor Binding Protein

Crystallography in Molecular Biology ◽

10.1007/978-1-4684-5272-3_36 ◽

1987 ◽

pp. 395-402

Author(s):

Abraham de Vos ◽

Sung-Hou Kim

Keyword(s):

Crystal Structure ◽

Receptor Binding ◽

Binding Protein ◽

Taste Receptor ◽

Sweet Taste ◽

Sweet Taste Receptor ◽

Receptor Binding Protein

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Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00163.2012 ◽

2012 ◽

Vol 303 (4) ◽

pp. E464-E474 ◽

Cited By ~ 49

Author(s):

Maartje C. P. Geraedts ◽

Tatsuyuki Takahashi ◽

Stephan Vigues ◽

Michele L. Markwardt ◽

Andongfac Nkobena ◽

...

Keyword(s):

Gastric Bypass ◽

Glycemic Control ◽

Large Intestine ◽

Molecular Mechanisms ◽

Hormone Secretion ◽

Taste Receptor ◽

Sweet Taste ◽

Oral Glucose ◽

Isolated Pancreatic Islets ◽

Sweet Taste Receptor

The glucose-dependent secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) is a critical step in the regulation of glucose homeostasis. Two molecular mechanisms have separately been suggested as the primary mediator of intestinal glucose-stimulated GLP-1 secretion (GSGS): one is a metabotropic mechanism requiring the sweet taste receptor type 2 (T1R2) + type 3 (T1R3) while the second is a metabolic mechanism requiring ATP-sensitive K+(KATP) channels. By quantifying sugar-stimulated hormone secretion in receptor knockout mice and in rats receiving Roux-en-Y gastric bypass (RYGB), we found that both of these mechanisms contribute to GSGS; however, the mechanisms exhibit different selectivity, regulation, and localization. T1R3−/−mice showed impaired glucose and insulin homeostasis during an oral glucose challenge as well as slowed insulin granule exocytosis from isolated pancreatic islets. Glucose, fructose, and sucralose evoked GLP-1 secretion from T1R3+/+, but not T1R3−/−, ileum explants; this secretion was not mimicked by the KATPchannel blocker glibenclamide. T1R2−/−mice showed normal glycemic control and partial small intestine GSGS, suggesting that T1R3 can mediate GSGS without T1R2. Robust GSGS that was KATPchannel-dependent and glucose-specific emerged in the large intestine of T1R3−/−mice and RYGB rats in association with elevated fecal carbohydrate throughout the distal gut. Our results demonstrate that the small and large intestines utilize distinct mechanisms for GSGS and suggest novel large intestine targets that could mimic the improved glycemic control seen after RYGB.

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