霊長類を含めた「うま味」受容の種間差

Two Distinct Determinants of Ligand Specificity in T1R1/T1R3 (the Umami Taste Receptor)

戸田 安香, 中北 智哉, 早川 卓志, 岡田 晋治, 成川 真隆, 今井 啓雄, 石丸 喜朗, 三坂 巧

　アミノ酸は栄養素の一つとして生物に重要な分子ですが、その受容は生物によって異なることが示唆されていました。例えばマウスとヒトを比べたときに、マウスは様々なアミノ酸に反応するのに対し、ヒトはグルタミン酸やアスパラギン酸など酸性アミノ酸に「うま味」として強く反応します。本研究では、アミノ酸受容体T1R1/T1R3の変異体を駆使して、その受容機構の基本構造を明らかにしました。結果として、様々なアミノ酸に対する応答を増強する部位と、酸性アミノ酸を結合する部位を発見しました。また、数種の霊長類のこれらの部位を比べたところ、霊長類の種によって受容するアミノ酸の種類や強度が異なることが示唆されました。

 この研究は東京大学農学生命科学研究科との共同利用・共同研究として実施されました。 
http://www.a.u-tokyo.ac.jp/topics/2014/20140109-1.html

The Journal of Biological Chemistry Vol. 288, No. 52, pp. 36863–36877, 2013

Umami taste perception in mammals is mediated by a heteromeric complex of two G-protein-coupled receptors, T1R1 and T1R3. T1R1/T1R3 exhibits species-dependent differences in ligand specificity; human T1R1/T1R3 specifically responds to L-Glu, whereas mouse T1R1/T1R3 responds more strongly to other L-amino acids than to L-Glu. The mechanism underlying this species difference remains unknown. In this study we analyzed chimeric human-mouse receptors and point mutants of T1R1/T1R3 and identified 12 key residues that modulate amino acid recognition in the human- and mouse-type responses in the extracellular Venus flytrap domain of T1R1. Molecular modeling revealed that the residues critical for human-type acidic amino acid recognition were located at the orthosteric ligand binding site. In contrast, all of the key residues for the mouse-type broad response were located at regions outside of both the orthosteric ligand binding site and the allosteric binding site for inosine-5′-monophosphate (IMP), a known natural umami taste enhancer. Site-directed mutagenesis demonstrated that the newly identified key residues for the mouse-type responses modulated receptor activity in a manner distinct from that of the allosteric modulation via IMP. Analyses of multiple point mutants suggested that the combination of two distinct determinants, amino acid selectivity at the orthosteric site and receptor activity modulation at the non-orthosteric sites, may mediate the ligand specificity of T1R1/T1R3. This hypothesis was supported by the results of studies using nonhuman primate T1R1 receptors. A complex molecular mechanism involving changes in the properties of both the orthosteric and non-orthosteric sites of T1R1 underlies the determination of ligand specificity in mammalian T1R1/T1R3.

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