{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T16:18:49Z","timestamp":1792167529697,"version":"4.4.0"},"reference-count":56,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,12]],"date-time":"2019-06-12T00:00:00Z","timestamp":1560297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN- 2014-04099"],"award-info":[{"award-number":["RGPIN- 2014-04099"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Bitter taste receptors (T2Rs) are expressed in several tissues of the body and are involved in a variety of roles apart from bitter taste perception. Advanced glycation end-products (AGEs) are produced by glycation of amino acids in proteins. There are varying sources of AGEs, including dietary food products, as well as endogenous reactions within our body. Whether these AGEs are T2R ligands remains to be characterized. In this study, we selected two AGEs, namely, glyoxal-derived lysine dimer (GOLD) and carboxymethyllysine (CML), based on their predicted interaction with the well-studied T2R4, and its physiochemical properties. Results showed predicted binding affinities (Kd) for GOLD and CML towards T2R4 in the nM and \u03bcM range, respectively. Calcium mobilization assays showed that GOLD inhibited quinine activation of T2R4 with IC50 10.52 \u00b1 4.7 \u03bcM, whilst CML was less effective with IC50 32.62 \u00b1 9.5 \u03bcM. To characterize whether this antagonism was specific to quinine activated T2R4 or applicable to other T2Rs, we selected T2R14 and T2R20, which are expressed at significant levels in different human tissues. A similar effect of GOLD was observed with T2R14; and in contrast, GOLD and CML activated T2R20 with an EC50 of 79.35 \u00b1 29.16 \u03bcM and 65.31 \u00b1 17.79 \u03bcM, respectively. In this study, we identified AGEs as novel T2R ligands that caused either activation or inhibition of different T2Rs.<\/jats:p>","DOI":"10.3390\/nu11061317","type":"journal-article","created":{"date-parts":[[2019,6,12]],"date-time":"2019-06-12T10:55:19Z","timestamp":1560336919000},"page":"1317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Advanced Glycation End-Products Can Activate or Block Bitter Taste Receptors"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1718-8551","authenticated-orcid":false,"given":"Appalaraju","family":"Jaggupilli","sequence":"first","affiliation":[{"name":"Manitoba Chemosensory Biology Research Group, Department of Oral Biology, University of Manitoba, Children\u2019s Hospital Research Institute of Manitoba (CHRIM), Winnipeg, MB R3E 0W4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Howard","sequence":"additional","affiliation":[{"name":"Manitoba Chemosensory Biology Research Group, Department of Oral Biology, University of Manitoba, Children\u2019s Hospital Research Institute of Manitoba (CHRIM), Winnipeg, MB R3E 0W4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9025-2513","authenticated-orcid":false,"given":"Rotimi E.","family":"Aluko","sequence":"additional","affiliation":[{"name":"Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1129-7957","authenticated-orcid":false,"given":"Prashen","family":"Chelikani","sequence":"additional","affiliation":[{"name":"Manitoba Chemosensory Biology Research Group, Department of Oral Biology, University of Manitoba, Children\u2019s Hospital Research Institute of Manitoba (CHRIM), Winnipeg, MB R3E 0W4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1073\/pnas.042617699","article-title":"Expression of bitter taste receptors of the t2r family in the gastrointestinal tract and enteroendocrine stc-1 cells","volume":"99","author":"Wu","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1093\/chemse\/bjr119","article-title":"Chemesthesis and the chemical senses as components of a \u201cchemofensor complex\u201d","volume":"37","author":"Green","year":"2012","journal-title":"Chem. Senses"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S0092-8674(00)80706-0","article-title":"T2rs function as bitter taste receptors","volume":"100","author":"Chandrashekar","year":"2000","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.biocel.2016.03.011","article-title":"Bitter taste receptors: Extraoral roles in pathophysiology","volume":"77","author":"Shaik","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"D1179","DOI":"10.1093\/nar\/gky974","article-title":"Bitterdb: Taste ligands and receptors database in 2019","volume":"47","author":"Nissim","year":"2019","journal-title":"Nucleic. Acids Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.biocel.2016.03.005","article-title":"Bitter taste receptors: Novel insights into the biochemistry and pharmacology","volume":"77","author":"Jaggupilli","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.cub.2010.04.043","article-title":"Modulation of bitter taste perception by a small molecule htas2r antagonist","volume":"20","author":"Slack","year":"2010","journal-title":"Curr. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14775","DOI":"10.1523\/JNEUROSCI.2923-11.2011","article-title":"Receptor agonism and antagonism of dietary bitter compounds","volume":"31","author":"Brockhoff","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1093\/chemse\/bjp092","article-title":"The molecular receptive ranges of human tas2r bitter taste receptors","volume":"35","author":"Meyerhof","year":"2010","journal-title":"Chem. Senses"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1080\/03639045.2018.1430822","article-title":"Use of polymers for taste-masking pediatric drug products","volume":"44","author":"Felton","year":"2018","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/j.chembiol.2017.08.004","article-title":"Blends of non-caloric sweeteners saccharin and cyclamate show reduced off-taste due to tas2r bitter receptor inhibition","volume":"24","author":"Behrens","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"25054","DOI":"10.1074\/jbc.M114.576975","article-title":"Amino acid derivatives as bitter taste receptor (t2r) blockers","volume":"289","author":"Pydi","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"516","DOI":"10.5483\/BMBRep.2008.41.7.516","article-title":"Identification of age-precursors and age formation in glycation-induced bsa peptides","volume":"41","author":"Ahmad","year":"2008","journal-title":"BMB Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1084\/jem.160.1.197","article-title":"Accumulation of diabetic rat peripheral nerve myelin by macrophages increases with the presence of advanced glycosylation endproducts","volume":"160","author":"Vlassara","year":"1984","journal-title":"J. Exp. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"912","DOI":"10.4315\/0362-028X.JFP-12-472","article-title":"Review of the characteristics of food-derived and endogenous ne-carboxymethyllysine","volume":"76","author":"Han","year":"2013","journal-title":"J. Food Prot."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"90","DOI":"10.4330\/wjc.v4.i4.90","article-title":"Role of advanced glycation end products in cardiovascular disease","volume":"4","author":"Hegab","year":"2012","journal-title":"World J. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"F645","DOI":"10.1152\/ajprenal.00398.2004","article-title":"Advanced glycation end products and the kidney","volume":"289","author":"Bohlender","year":"2005","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_18","first-page":"1025","article-title":"Advanced glycation endproducts and cigarette smoking","volume":"44","author":"Nicholl","year":"1998","journal-title":"Cell Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.jada.2010.03.018","article-title":"Advanced glycation end products in foods and a practical guide to their reduction in the diet","volume":"110","author":"Uribarri","year":"2010","journal-title":"J. Am. Diet Assoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1089\/rej.2009.0846","article-title":"Characteristics, formation, and pathophysiology of glucosepane: A major protein cross-link","volume":"12","author":"Sjoberg","year":"2009","journal-title":"Rejuvenation Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1749-6632.1997.tb51994.x","article-title":"Atherogenesis and advanced glycation: Promotion, progression, and prevention","volume":"811","author":"Stitt","year":"1997","journal-title":"Ann. N Y Acad. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s001250051591","article-title":"Advanced glycation end-products: A review","volume":"44","author":"Singh","year":"2001","journal-title":"Diabetologia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10872","DOI":"10.1021\/bi00034a021","article-title":"Epsilon.-(carboxymethyl) lysine is a dominant advanced glycation end product (age) antigen in tissue proteins","volume":"34","author":"Reddy","year":"1995","journal-title":"Biochemistry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1159\/000324846","article-title":"Endogenous secretory receptor for advanced glycation end products and chronic kidney disease in the elderly population","volume":"33","author":"Dalal","year":"2011","journal-title":"Am. J. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1021\/bi00219a007","article-title":"Age-dependent accumulation of n epsilon-(carboxymethyl)lysine and n epsilon-(carboxymethyl)hydroxylysine in human skin collagen","volume":"30","author":"Dunn","year":"1991","journal-title":"Biochemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1002\/psc.519","article-title":"Peptide and amino acid glycation: New insights into the maillard reaction","volume":"10","author":"Horvat","year":"2004","journal-title":"J. Pept. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.3390\/nu2121247","article-title":"Dietary advanced glycation end products and aging","volume":"2","year":"2010","journal-title":"Nutrients"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"327","DOI":"10.2353\/ajpath.2008.080152","article-title":"Oral glycotoxins determine the effects of calorie restriction on oxidant stress, age-related diseases, and lifespan","volume":"173","author":"Cai","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4902","DOI":"10.1021\/acs.jafc.8b00830","article-title":"Beef protein-derived peptides as bitter taste receptor t2r4 blockers","volume":"66","author":"Zhang","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.foodchem.2019.01.059","article-title":"Hen protein-derived peptides as the blockers of human bitter taste receptors t2r4, t2r7 and t2r14","volume":"283","author":"Xu","year":"2019","journal-title":"Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1126\/science.1173869","article-title":"Motile cilia of human airway epithelia are chemosensory","volume":"325","author":"Shah","year":"2009","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1038\/nm.2237","article-title":"Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction","volume":"16","author":"Deshpande","year":"2010","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.ejphar.2014.07.005","article-title":"Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle","volume":"740","author":"Manson","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Foster, S.R., Porrello, E.R., Purdue, B., Chan, H.W., Voigt, A., Frenzel, S., Hannan, R.D., Moritz, K.M., Simmons, D.G., and Molenaar, P. (2013). Expression, regulation and putative nutrient-sensing function of taste gpcrs in the heart. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064579"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1183\/09031936.00077712","article-title":"Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics","volume":"42","author":"James","year":"2013","journal-title":"Eur. Respir. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.pharmthera.2013.11.004","article-title":"Extrasensory perception: Odorant and taste receptors beyond the nose and mouth","volume":"142","author":"Foster","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s11010-016-2902-z","article-title":"Analysis of the expression of human bitter taste receptors in extraoral tissues","volume":"426","author":"Jaggupilli","year":"2017","journal-title":"Mol. Cell Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1096\/fj.13-242594","article-title":"The bitter pill: Clinical drugs that activate the human bitter taste receptor tas2r14","volume":"28","author":"Levit","year":"2014","journal-title":"FASEB J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/cbdd.12293","article-title":"Identification of novel compounds for human bitter taste receptors","volume":"84","author":"Ji","year":"2014","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12174","DOI":"10.1038\/s41598-017-11720-0","article-title":"Identification of a specific agonist of human tas2r14 from radix bupleuri through virtual screening, functional evaluation and binding studies","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1096\/fj.201800521RR","article-title":"Chemosensory bitter taste receptors (t2rs) are activated by multiple antibiotics","volume":"33","author":"Jaggupilli","year":"2019","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1021\/acsinfecdis.8b00094","article-title":"Characterization of the binding sites for bacterial acyl homoserine lactones (ahls) on human bitter taste receptors (t2rs)","volume":"4","author":"Jaggupilli","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Upadhyaya, J.D., Chakraborty, R., Shaik, F.A., Jaggupilli, A., Bhullar, R.P., and Chelikani, P. (2016). The pharmacochaperone activity of quinine on bitter taste receptors. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156347"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/bs.mie.2014.12.013","article-title":"Expression of g protein-coupled receptors in mammalian cells","volume":"556","author":"Chakraborty","year":"2015","journal-title":"Methods Enzymol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.bbamem.2018.01.014","article-title":"Plasticity of the ligand binding pocket in the bitter taste receptor t2r7","volume":"5","author":"Liu","year":"2018","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s11010-018-3273-4","article-title":"Study of adenylyl cyclase-galphas interactions and identification of novel ac ligands","volume":"446","author":"Jaggupilli","year":"2018","journal-title":"Mol. Cell Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1002\/jcc.540130714","article-title":"Validation of the general-purpose quanta(r)3.2\/charmm(r) force-field","volume":"13","author":"Momany","year":"1992","journal-title":"J. Comput. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/978-1-62703-059-5_14","article-title":"Developmental toxicity prediction","volume":"930","author":"Venkatapathy","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1002\/jcc.10306","article-title":"Detailed analysis of grid-based molecular docking: A case study of cdocker-a charmm-based md docking algorithm","volume":"24","author":"Wu","year":"2003","journal-title":"J. Comput. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.jmgm.2014.04.014","article-title":"Identification of a high affinity selective inhibitor of polo-like kinase 1 for cancer chemotherapy by computational approach","volume":"51","author":"Kumar","year":"2014","journal-title":"J. Mol. Graph. Model."},{"key":"ref_51","unstructured":"(2019, May 20). Pymol: An Open-Source Molecular Graphics Tool. Available online: https:\/\/www.ccp4.ac.uk\/newsletters\/newsletter40\/11_pymol.pdf."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8814","DOI":"10.1021\/acs.jafc.8b03569","article-title":"Human bitter taste receptors are activated by different classes of polyphenols","volume":"66","author":"Soares","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/cbdd.12734","article-title":"Probing the binding pocket of the broadly tuned human bitter taste receptor tas2r14 by chemical modification of cognate agonists","volume":"88","author":"Karaman","year":"2016","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8636","DOI":"10.1021\/jf904240c","article-title":"Advanced glycation end products down-regulate gap junctions in human hepatoma skhep 1 cells via the activation of src-dependent erk1\/2 and jnk\/sapk\/ap1 signaling pathways","volume":"58","author":"Lin","year":"2010","journal-title":"J. Agric. Food Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s12307-018-0214-4","article-title":"Skewed signaling through the receptor for advanced glycation end-products alters the proinflammatory profile of tumor-associated macrophages","volume":"11","author":"Rojas","year":"2018","journal-title":"Cancer Microenviron."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s12672-018-0342-9","article-title":"Rage and its ligands: Molecular interplay between glycation, inflammation, and hallmarks of cancer-a review","volume":"9","author":"Palanissami","year":"2018","journal-title":"Horm. Cancer"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/6\/1317\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:57:51Z","timestamp":1760187471000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/6\/1317"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,12]]},"references-count":56,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["nu11061317"],"URL":"https:\/\/doi.org\/10.3390\/nu11061317","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,12]]}}}