Molecular mechanism of species-dependent sweet taste toward artificial sweeteners.
Molecular mechanism of species-dependent sweet taste toward artificial sweeteners.
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DOI：
10.1523/jneurosci.0791-11.2011
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发表时间：
2011-07-27
期刊：
影响因子：
--
通讯作者：
Cui M
中科院分区：
文献类型：
--
作者：
Liu B;Ha M;Meng XY;Kaur T;Khaleduzzaman M;Zhang Z;Jiang P;Li X;Cui M
Tas 1 R2和Tas 1 R3的异二聚体是广泛作用的甜味受体，其介导哺乳动物对天然和人工甜味剂和甜味蛋白的甜味。甜味感知是一种物种选择性的生理过程。例如，人造甜味剂甜菊糖和纽甜对人类、猿和旧世界的猴子来说是甜的，但对新世界的猴子和啮齿动物来说不是。虽然已经确定了这些甜味剂激活受体的特定区域，但物种依赖性甜味的分子机制仍然难以捉摸。使用人/松鼠猴嵌合体，诱变和分子建模，我们揭示了不同的反应，哺乳动物物种对人工甜味剂甜和纽甜的配体结合口袋中的几个残基的组合的空间效应。发现人Tas 1 R2中的残基S40和D142（对应于松鼠猴Tas 1 R2中的残基T40和E142）是甜味的种属依赖性差异的关键残基。此外，人Tas 1 R2残基I67（对应于松鼠猴受体中的S67）调节纽甜的亲和力高于西莫司坦。本研究不仅揭示了人工甜味剂甜味的物种依赖性分子机制，而且为设计新型有效的人工甜味化合物提供了指导。
The heterodimer of Tas1R2 and Tas1R3 is a broadly acting sweet taste receptor, which mediates mammalian sweet taste toward natural and artificial sweeteners and sweet-tasting proteins. Perception of sweet taste is a species selective physiological process. For instance, artificial sweeteners aspartame and neotame taste sweet to humans, apes and Old World monkeys but not to New World monkeys and rodents. Although specific regions determining the activation of the receptors by these sweeteners have been identified, the molecular mechanism of species-dependent sweet taste remains elusive. Using human/squirrel monkey chimeras, mutagenesis and molecular modeling, we reveal that the different responses of mammalian species towards the artificial sweeteners aspartame and neotame are determined by the steric effect of a combination of a few residues in the ligand binding pocket. Residues S40 and D142 in the human Tas1R2, which correspond to residues T40 and E142 in the squirrel monkey Tas1R2, were found to be the critical residues for the species dependent difference in sweet taste. In addition, human Tas1R2 residue I67, which corresponds to S67 in squirrel monkey receptor, modulates the higher affinity of neotame than that of aspartame. Our studies not only shed light on the molecular mechanism of species dependent sweet taste toward artificial sweeteners, but also provide guidance for designing novel effective artificial sweet compounds.