{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:40Z","timestamp":1787028460961,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["236360313"],"award-info":[{"award-number":["236360313"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: Amino acids have a central role in cell metabolism, and intracellular changes contribute to the pathogenesis of various diseases, while the role and specific organ distribution of dipeptides is largely unknown. Method: We established a sensitive, rapid and reliable UPLC-MS\/MS method for quantification of 36 dipeptides. Dipeptide patterns were analyzed in brown and white adipose tissues, brain, eye, heart, kidney, liver, lung, muscle, sciatic nerve, pancreas, spleen and thymus, serum and urine of C57BL\/6N wildtype mice and related to the corresponding amino acid profiles. Results: A total of 30 out of the 36 investigated dipeptides were detected with organ-specific distribution patterns. Carnosine and anserine were most abundant in all organs, with the highest concentrations in muscles. In liver, Asp-Gln and Ala-Gln concentrations were high, in the spleen and thymus, Glu-Ser and Gly-Asp. In serum, dipeptide concentrations were several magnitudes lower than in organ tissues. In all organs, dipeptides with C-terminal proline (Gly-Pro and Leu-Pro) were present at higher concentrations than dipeptides with N-terminal proline (Pro-Gly and Pro-Leu). Organ-specific amino acid profiles were related to the dipeptide profile with several amino acid concentrations being related to the isomeric form of the dipeptides. Aspartate, histidine, proline and serine tissue concentrations correlated with dipeptide concentrations, when the amino acids were present at the C- but not at the N-terminus. Conclusion: Our multi-dipeptide quantification approach demonstrates organ-specific dipeptide distribution. This method allows us to understand more about the dipeptide metabolism in disease or in healthy state.<\/jats:p>","DOI":"10.3390\/ijms22189979","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T21:47:11Z","timestamp":1631742431000},"page":"9979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A Novel UPLC-MS\/MS Method Identifies Organ-Specific Dipeptide Profiles"],"prefix":"10.3390","volume":"22","author":[{"given":"Elena","family":"Heidenreich","sequence":"first","affiliation":[{"name":"Centre for Organismal Studies (COS), Metabolomics Core Technology Platform, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilman","family":"Pfeffer","sequence":"additional","affiliation":[{"name":"Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2752-1597","authenticated-orcid":false,"given":"Tamara","family":"Kracke","sequence":"additional","affiliation":[{"name":"Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Mechtel","sequence":"additional","affiliation":[{"name":"Centre for Organismal Studies (COS), Metabolomics Core Technology Platform, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Nawroth","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I and Clinical Chemistry, University Hospital of Heidelberg, 69120 Heidelberg, Germany"},{"name":"German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany"},{"name":"Institute for Diabetes and Cancer (IDC) Helmholtz Center Munich, 85764 Neuherberg, Germany"},{"name":"Joint Heidelberg-Institute for Diabetes and Cancer (IDC) Translational Diabetes Program, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg F","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus Peter","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6238-4818","authenticated-orcid":false,"given":"R\u00fcdiger","family":"Hell","sequence":"additional","affiliation":[{"name":"Centre for Organismal Studies (COS), Metabolomics Core Technology Platform, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-0865","authenticated-orcid":false,"given":"Gernot","family":"Poschet","sequence":"additional","affiliation":[{"name":"Centre for Organismal Studies (COS), Metabolomics Core Technology Platform, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4649-0848","authenticated-orcid":false,"given":"Verena","family":"Peters","sequence":"additional","affiliation":[{"name":"Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/biof.1554","article-title":"Proline-containing peptides\u2014New insight and implications: A Review","volume":"45","author":"Misiura","year":"2019","journal-title":"Biofactors"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1002\/cphy.c170032","article-title":"Function, regulation, and pathophysiological relevance of the pot superfamily, specifically pept1 in inflammatory bowel disease","volume":"8","author":"Viennois","year":"2018","journal-title":"Compr. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1002\/cphy.c170038","article-title":"Proton coupled oligopeptide transporter 1 (pept1) function, regulation, and influence on the intestinal homeostasis","volume":"8","author":"Spanier","year":"2018","journal-title":"Compr. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.2147\/DDDT.S151725","article-title":"Regulation profile of the intestinal peptide transporter 1 (PepT1)","volume":"11","author":"Wang","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e1900263","DOI":"10.1002\/mnfr.201900263","article-title":"Transport versus hydrolysis: Reassessing intestinal assimilation of Di- and Tripeptides by LC-MS\/MS analysis","volume":"63","author":"Rohm","year":"2019","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1801094","DOI":"10.1002\/mnfr.201801094","article-title":"Appearance of Di- and tripeptides in human plasma after a protein meal does not correlate with pept1 substrate selectivity","volume":"63","author":"Rohm","year":"2019","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"771","DOI":"10.2174\/1389203719666180226155657","article-title":"Biosynthesis of carnosine and related dipeptides in vertebrates","volume":"19","author":"Kwiatkowski","year":"2018","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.tibs.2018.05.003","article-title":"Amino acid transporters revisited: New views in health and disease","volume":"43","author":"Kandasamy","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/s10545-017-0063-1","article-title":"Amino acid synthesis deficiencies","volume":"40","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1021\/ac901790q","article-title":"Sensitive and rapid method for amino acid quantitation in malaria biological samples using AccQ. Tag ultra performance liquid chromatography-electrospray ionization-MS\/MS with multiple reaction monitoring","volume":"82","author":"Armenta","year":"2010","journal-title":"Anal. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s11306-018-1374-4","article-title":"A targeted metabolomic procedure for amino acid analysis in different biological specimens by ultra-high-performance liquid chromatography-tandem mass spectrometry","volume":"14","author":"Casado","year":"2018","journal-title":"Metabolomics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-1-61779-445-2_2","article-title":"Combination of an AccQ\u00b7Tag-ultra performance liquid chromatographic method with tandem mass spectrometry for the analysis of amino acids","volume":"828","author":"Salazar","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Weigand, T., Colbatzky, F., Pfeffer, T., Garbade, S.F., Klingbeil, K., Colbatzky, F., Becker, M., Zemva, J., Bulkescher, R., and Sch\u00fcrfeld, R. (2020). A global Cndp1-knock-out selectively increases renal carnosine and anserine concentrations in an age- and gender-specific manner in mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144887"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1152\/physrev.00039.2012","article-title":"Physiology and pathophysiology of carnosine","volume":"93","author":"Boldyrev","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/S0950-351X(96)80771-3","article-title":"Protein metabolism and liver disease","volume":"10","author":"Charlton","year":"1996","journal-title":"Baillieres Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R., and Newsholme, P. (2018). Glutamine: Metabolism and immune function, supplementation and clinical translation. Nutrients, 10.","DOI":"10.20944\/preprints201809.0459.v1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/0026-0495(94)90051-5","article-title":"Importance of liver and kidney for the utilization of glutamine-containing dipeptides in man","volume":"43","author":"Druml","year":"1994","journal-title":"Metabolism"},{"key":"ref_18","first-page":"Cd007605","article-title":"Nutritional interventions for liver-transplanted patients","volume":"8","author":"Langer","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S568","DOI":"10.1097\/01.CCM.0000278600.14265.95","article-title":"Specific amino acids in the critically ill patient\u2014Exogenous glutamine\/arginine: A common denominator?","volume":"35","author":"Vermeulen","year":"2007","journal-title":"Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Herzog, R., Bartosova, M., Tarantino, S., Wagner, A., Unterwurzacher, M., Sacnun, J.M., Lichtenauer, A.M., Kuster, L., Schaefer, B., and Alper, S.L. (2020). Peritoneal Dialysis fluid supplementation with alanyl-glutamine attenuates conventional dialysis fluid-mediated endothelial cell injury by restoring perturbed cytoprotective responses. Biomolecules, 10.","DOI":"10.3390\/biom10121678"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.clnesp.2016.09.007","article-title":"Glutamine dipeptide-supplemented parenteral nutrition improves the clinical outcomes of critically ill patients: A systematic evaluation of randomised controlled trials","volume":"17","author":"Stehle","year":"2017","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1097\/MCO.0000000000000383","article-title":"Glycine metabolism in skeletal muscle: Implications for metabolic homeostasis","volume":"20","author":"Koopman","year":"2017","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_23","first-page":"833798","article-title":"Serine and glycine are essential for human muscle progenitor cell population expansion","volume":"3","author":"Gheller","year":"2019","journal-title":"bioRxiv"},{"key":"ref_24","first-page":"120","article-title":"Arginine-dependent immune responses","volume":"9","author":"Reith","year":"2021","journal-title":"Cell Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1159\/000321319","article-title":"Brown versus white adipose tissue: A mini-review","volume":"58","author":"Saely","year":"2012","journal-title":"Gerontology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1016\/S0261-5614(03)00147-X","article-title":"The role of amino acids and synthetic dipeptides","volume":"22","year":"2003","journal-title":"Clin. Nutr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00253-008-1590-3","article-title":"Synthesis and application of dipeptides; current status and perspectives","volume":"81","author":"Yagasaki","year":"2008","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.4155\/fmc-2016-0088","article-title":"Computational approaches in the rational design of improved carbonyl quenchers: Focus on histidine containing dipeptides","volume":"8","author":"Vistoli","year":"2016","journal-title":"Future Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.2174\/0929867326666190326111851","article-title":"Carnosine and diabetic nephropathy","volume":"27","author":"Peters","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1007\/s00726-011-1046-4","article-title":"Carnosine treatment largely prevents alterations of renal carnosine metabolism in diabetic mice","volume":"42","author":"Peters","year":"2012","journal-title":"Amino Acids"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Peters, V., Calabrese, V., Forsberg, E., Volk, N., Fleming, T., Baelde, H., Weigand, T., Thiel, C., Trovato, A., and Scuto, M. (2018). Protective actions of anserine under diabetic conditions. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092751"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e13779","DOI":"10.1111\/jfbc.13779","article-title":"Study on the domain selective inhibition of angiotensin-converting enzyme (ACE) by food-derived tyrosine-containing dipeptides","volume":"45","author":"Song","year":"2021","journal-title":"J. Food Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e106800","DOI":"10.15252\/embj.2020106800","article-title":"Tyr-Asp inhibition of glyceraldehyde 3-phosphate dehydrogenase affects plant redox metabolism","volume":"40","author":"Moreno","year":"2021","journal-title":"EMBO J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s10815-011-9705-7","article-title":"Dipeptide forms of glycine support mouse preimplantation embryo development in vitro and provide protection against high media osmolality","volume":"29","author":"Moravek","year":"2012","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"c108","DOI":"10.1159\/000078639","article-title":"Elevated epsilon-(gamma-glutamyl) lysine in human diabetic nephropathy results from increased expression and cellular release of tissue transglutaminase","volume":"97","author":"Skill","year":"2004","journal-title":"Nephron Clin. Pract."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"709","DOI":"10.2174\/1573406414666180309153142","article-title":"Synthesis of a tyr-tyr dipeptide library and evaluation against tumor cells","volume":"14","author":"Vasconcelos","year":"2018","journal-title":"Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ano, Y., Yoshino, Y., Uchida, K., and Nakayama, H. (2019). Preventive effects of tryptophan-methionine dipeptide on neural inflammation and Alzheimer\u2019s pathology. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133206"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1471-4159.2008.05350.x","article-title":"Increased levels of gamma-glutamylamines in Huntington disease CSF","volume":"106","author":"Jeitner","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3056","DOI":"10.1111\/febs.14596","article-title":"Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia","volume":"285","author":"Pfeffer","year":"2018","journal-title":"FEBS J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"609806","DOI":"10.3389\/fmolb.2020.609806","article-title":"Distinctive metabolomics patterns associated with insulin resistance and type 2 diabetes mellitus","volume":"7","author":"Gu","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1039\/C5FO01530H","article-title":"Dietary protein intake and human health","volume":"7","author":"Wu","year":"2016","journal-title":"Food Funct."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Weger, B.D., Weger, M., G\u00f6rling, B., Schink, A., Gobet, C., Keime, C., Poschet, G., Jost, B., Krone, N., and Hell, R. (2016). Extensive regulation of diurnal transcription and metabolism by glucocorticoids. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1006512"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9979\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:00:23Z","timestamp":1760166023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/9979"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,15]]},"references-count":42,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22189979"],"URL":"https:\/\/doi.org\/10.3390\/ijms22189979","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,15]]}}}