Extracellular Calcium Receptor as a Target for Glutathione and Its Derivatives

Goralski, Thomas J.; Ram, Jeffrey L.

doi:10.3390/ijms23020717

Cited by 10 publications

(11 citation statements)

References 86 publications

(126 reference statements)

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“…The calcium-sensing receptor (CaSR) is the receptor for kokumi substances; the extracellular domain of human CaSR (residue 22–539), known as the Venus flytrap (VFT) domain, binds to kokumi active molecules and participates in molecular initiation events , of kokumi sensing. Docking results of the kokumi molecules and non-kokumi molecules to CaSR (Figure C) revealed that former had a stronger affinity ( P < 0.01).…”

Section: Resultsmentioning

confidence: 99%

Building a Kokumi Database and Machine Learning-Based Prediction: A Systematic Computational Study on Kokumi Analysis

He,

Liu,

et al. 2024

J. Chem. Inf. Model.

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Kokumi is a subtle sensation characterized by a sense of fullness, continuity, and thickness. Traditional methods of taste discovery and analysis, including those of kokumi, have been labor-intensive and costly, thus necessitating the emergence of computational methods as critical strategies in molecular taste analysis and prediction. In this study, we undertook a comprehensive analysis, prediction, and screening of the kokumi compounds. We categorized 285 kokumi compounds from a previously unreleased kokumi database into five groups based on their molecular characteristics. Moreover, we predicted kokumi/ non-kokumi and multi-flavor compositions using six structure− taste relationship models: MLP-E3FP, MLP-PLIF, MLP-RDKFP, SVM-RDKFP, RF-RDKFP, and WeaveGNN feature of Atoms and Bonds. These six predictors exhibited diverse performance levels across two different models. For kokumi/non-kokumi prediction, the WeaveGNN model showed an exceptional predictive AUC value (0.94), outperforming the other models (0.87, 0.90, 0.89, 0.92, and 0.78). For multi-flavor prediction, the MLP-E3FP model demonstrated a higher predictive AUC and MCC value (0.94 and 0.74) than the others (0.73 and 0.33; 0.92 and 0.70; 0.95 and 0.73; 0.94 and 0.64; and 0.88 and 0.69). This data highlights the model's proficiency in accurately predicting kokumi molecules. As a result, we sourced kokumi active compounds through a highthroughput screening of over 100 million molecules, further refined by toxicity and similarity screening. Lastly, we launched a web platform, KokumiPD (https://www.kokumipd.com/), offering a comprehensive kokumi database and online prediction services for users.

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Section: Resultsmentioning

confidence: 99%

Building a Kokumi Database and Machine Learning-Based Prediction: A Systematic Computational Study on Kokumi Analysis

He,

Liu,

et al. 2024

J. Chem. Inf. Model.

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“…Similarly, GSH and GSSG also showed dose-dependent competition (Figure D,E). Moreover, glutathione-Cys disulfide (CysSG) reduced the DAZ-G conjugation to CaSR (Figure S3B). Their competing concentrations are comparable to concentrations of individual compounds for CaSR activation (EC 50 = 0.3 mM, 0.1 μM, and 0.3 μM for l -Phe, GSH, and GSSG). , In contrast, the DAZ-G conjugation to CaSR was not reduced by cinacalcet nor etelcalcetide at concentrations close to their EC 50 values (0.05 and 0.5 μM, respectively , ) (Figure F,G).…”

Section: Resultsmentioning

confidence: 99%

Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor

Matarage Don,

Padmavathi,

Khasro

et al. 2024

ACS Chem. Biol.

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The calcium-sensing receptor (CaSR), abundantly expressed in the parathyroid gland and kidney, plays a central role in calcium homeostasis. In addition, CaSR exerts multimodal roles, including inflammation, muscle contraction, and bone remodeling, in other organs and tissues. The diverse functions of CaSR are mediated by many endogenous and exogenous ligands, including calcium, amino acids, glutathione, cinacalcet, and etelcalcetide, that have distinct binding sites in CaSR. However, strategies to evaluate ligand interactions with CaSR remain limited. Here, we developed a glutathione-based photoaffinity probe, DAZ-G, that analyzes ligand binding to CaSR. We showed that DAZ-G binds to the amino acid binding site in CaSR and acts as a positive allosteric modulator of CaSR. Oxidized and reduced glutathione and phenylalanine effectively compete with DAZ-G conjugation to CaSR, while calcium, cinacalcet, and etelcalcetide have cooperative effects. An unexpected finding was that caffeine effectively competes with DAZ-G′s conjugation to CaSR and acts as a positive allosteric modulator of CaSR. The effective concentration of caffeine for CaSR activation (<10 μM) is easily attainable in plasma by ordinary caffeine consumption. Our report demonstrates the utility of a new chemical probe for CaSR and discovers a new protein target of caffeine, suggesting that caffeine consumption can modulate the diverse functions of CaSR.

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“…Structural modeling studies also suggested that γ-glutamyl peptides such as glutathione, oxidized glutathione, and oxidized glutathione derivative L-cysteine glutathione disulfide likely bind at the same hinge region of the CaSR ECD. [114][115][116] It is possible that CaSR may also have the capacity to distinguish between oxidizing and reducing cellular environments. 116 The identification of potential anion binding sites by Zhang et al 111 (e.g., HCO 3…”

Section: Structural and Regulation Advances Of Casr And The Ligand-bi...mentioning

confidence: 99%

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

Tian,

Andrews,

Yan

et al. 2024

Chronic Diseases and Translational Medicine

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Calcium‐sensing receptor (CaSR), a family C G‐protein‐coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L‐Trp and L‐Phe), small peptides, anions (e.g., HCO3− and PO43−), and pH. CaSR‐mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein–protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+‐dependent cellular physiological processes and in CaSR‐dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G‐protein‐coupled receptors.

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Extracellular Calcium Receptor as a Target for Glutathione and Its Derivatives

Cited by 10 publications

References 86 publications

Building a Kokumi Database and Machine Learning-Based Prediction: A Systematic Computational Study on Kokumi Analysis

Building a Kokumi Database and Machine Learning-Based Prediction: A Systematic Computational Study on Kokumi Analysis

Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

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