Positive/Negative Allosteric Modulation Switching in an Umami Taste Receptor (T1R1/T1R3) by a Natural Flavor Compound, Methional

Toda, Yasuka; Nakagita, Tomoya; Hirokawa, Takatsugu; Yamashita, Yūki; Nakajima, Ayako; Narukawa, Masataka; Ishimaru, Yoshiro; Uchida, Riichiro; Misaka, Takumi

doi:10.1038/s41598-018-30315-x

Cited by 32 publications

(25 citation statements)

References 33 publications

(55 reference statements)

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“…To date, because of the high structural homology between various TM protein classes even with distant homologs [349], the rational design of novel therapeutic candidates has been facilitated by comparative modeling combined with docking approaches and machine learning algorithms [350][351][352][353]. While currently repurposed ligands generally target primary orthosteric sites [343,354], long unbiased MD simulations have also facilitated the identification of allosteric regions of membrane proteins that may potentiate or inhibit downstream signal transduction [355,356].…”

Section: Molecular Dynamics Simulations Of Gpcrs and Ion Channelsmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.

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Section: Molecular Dynamics Simulations Of Gpcrs and Ion Channelsmentioning

confidence: 99%

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

et al. 2020

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“…Despite the variation in the amino acid type and location important for agonist binding among receptors of the bitter (Li et al, 2002;Nelson et al, 2002;Zhang et al, 2008) Cyclamate Sodium cyclohexylsulfamate 8 TMD (TAS1R3) (Xu et al, 2004) Methional (3-methylsulfanylpropanal) -0.12 TMD (TAS1R3) (Toda et al, 2018) Lactisole (2-4-methoxyphenoxy propionic acid)…”

Section: Bitter Receptors Ligand Binding Domain and Amino Acid Residuesmentioning

confidence: 99%

“…In contrast to IMP and GMP that bind to the TAS1R1 extracellular domain, the well-known flavor compound methional and its analogs bind to the TMD region and allosterically regulate the umami receptor in a species dependent manner ( Toda et al, 2018 ). Importantly, methional utilizes several distinct residues in different TAS1R1 transmembrane domains (TMD2-7) to act as a PAM in the human umami receptor, yet it behaves as a NAM in the mouse counterpart.…”

Section: Umami Taste Signal Transduction Mechanismsmentioning

confidence: 99%

“…Importantly, methional utilizes several distinct residues in different TAS1R1 transmembrane domains (TMD2-7) to act as a PAM in the human umami receptor, yet it behaves as a NAM in the mouse counterpart. This unusual phenomenon provided an opportunity to study the mechanisms of both positive and negative modulation in TAS1R1 simultaneously ( Toda et al, 2018 ).…”

Section: Umami Taste Signal Transduction Mechanismsmentioning

confidence: 99%

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G Protein-Coupled Receptors in Taste Physiology and Pharmacology

2020

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Heterotrimeric G protein-coupled receptors (GPCRs) comprise the largest receptor family in mammals and are responsible for the regulation of most physiological functions. Besides mediating the sensory modalities of olfaction and vision, GPCRs also transduce signals for three basic taste qualities of sweet, umami (savory taste), and bitter, as well as the flavor sensation kokumi. Taste GPCRs reside in specialised taste receptor cells (TRCs) within taste buds. Type I taste GPCRs (TAS1R) form heterodimeric complexes that function as sweet (TAS1R2/TAS1R3) or umami (TAS1R1/TAS1R3) taste receptors, whereas Type II are monomeric bitter taste receptors or kokumi/calcium-sensing receptors. Sweet, umami and kokumi receptors share structural similarities in containing multiple agonist binding sites with pronounced selectivity while most bitter receptors contain a single binding site that is broadly tuned to a diverse array of bitter ligands in a non-selective manner. Tastant binding to the receptor activates downstream secondary messenger pathways leading to depolarization and increased intracellular calcium in TRCs, that in turn innervate the gustatory cortex in the brain. Despite recent advances in our understanding of the relationship between agonist binding and the conformational changes required for receptor activation, several major challenges and questions remain in taste GPCR biology that are discussed in the present review. In recent years, intensive integrative approaches combining heterologous expression, mutagenesis and homology modeling have together provided insight regarding agonist binding site locations and molecular mechanisms of orthosteric and allosteric modulation. In addition, studies based on transgenic mice, utilizing either global or conditional knock out strategies have provided insights to taste receptor signal transduction mechanisms and their roles in physiology. However, the need for more functional studies in a physiological context is apparent and would be enhanced by a crystallized structure of taste receptors for a more complete picture of their pharmacological mechanisms.

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“…Steinhaus and Schieberle (2007) suggested that 3-methyl-1-butanol (3-Me-BuOH), 3-hydroxy-4,5dimethyl-2(5H)-furanone (sotolone), 4-hydroxy-2 (or 5)-ethyl-5 (or 2)-methyl-3 (2H)-furanone (HEMF), 2-methyl butanal, and 3-(methylsulfanyl) propanal (methional) were the most important aromatic components in soy sauce. Toda et al (2018) reported that methional enhances the umami taste by interacting with the transmembrane domain of a subunit of the umami receptor, T1R1. Sotolone has been reported to enhance saltiness because its odor is congruent with saltiness (Batenburg & Van der Velden, 2011).…”

Section: Introductionmentioning

confidence: 99%

Contribution of the retronasal odor of soy sauce to salt reduction

Manabe

Sakaue

Obata

2020

Journal of Food Science

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The characteristic odor of soy sauce has been reported to enhance saltiness. However, soy sauce is used not only as a sauce that is added directly to food, but also as a seasoning. In addition, some of the aromatic compounds that contribute to the soy sauce odor change during cooking or heating. In the present study, the effects of the retronasal odor of uncooked and cooked soy sauce on the enhancement of saltiness and palatability of a low‐salt solution were sensory evaluated. A probit analysis indicated that the saltiness‐enhancing effect of the odor of 15% uncooked soy sauce was lost by heating. The odors of soy sauce boiled for 10 min (cooked SS) and the residue of soy sauce heated at 200 °C for 1 min improved the palatability of the low‐salt solution. Gas chromatography (GC) analyses, namely, GC–olfactometry and GC–mass spectrometry, showed that one active candidate aromatic component of soy sauce contributing to saltiness enhancement was 3‐methyl‐1‐butanol (3‐Me‐BuOH). The saltiness‐enhancing effects of cooked SS could be restored by adding 3‐Me‐BuOH, as assessed by the sensory evaluation. These data demonstrated that 3‐Me‐BuOH contributes to saltiness enhancement. Practical Application We found that the odor of cooked soy sauce could improve the palatability of low‐salt food. Although the saltiness‐enhancing effect provided by the odor of uncooked soy sauce was lost, the saltiness‐enhancing effect of the odor of cooked soy sauce can be partially restored by adding 3‐methyl butanol. Thus, not only the odor of unheated soy sauce but also the odor of heated soy sauce following addition of 3‐methyl butanol may be useful for developing palatable salt‐reduced food.

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Positive/Negative Allosteric Modulation Switching in an Umami Taste Receptor (T1R1/T1R3) by a Natural Flavor Compound, Methional

Cited by 32 publications

References 33 publications

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

G Protein-Coupled Receptors in Taste Physiology and Pharmacology

Contribution of the retronasal odor of soy sauce to salt reduction

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