{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:18:52Z","timestamp":1791587932559,"version":"4.3.4"},"reference-count":106,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T00:00:00Z","timestamp":1612224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Protein substitutes developed for phenylketonuria (PKU) are a synthetic source of protein commonly based on L-amino acids. They are essential in the treatment of phenylketonuria (PKU) and other amino acid disorders, allowing the antagonistic amino acid to be removed but with the safe provision of all other amino acids necessary for maintaining normal physiological function. They were first formulated by a chemist and used experimentally on a 2-year-old girl with PKU and their nutritional formulations and design have improved over time. Since 2008, a bioactive macropeptide has been used as a base for protein substitutes in PKU, with potential benefits of improved bone and gut health, nitrogen retention, and blood phenylalanine control. In 2018, animal studies showed that physiomimic technology coating the amino acids with a polymer allows a slow release of amino acids with an improved physiological profile. History has shown that in PKU, the protein substitute\u2019s efficacy is determined by its nutritional profile, amino acid composition, dose, timing, distribution, and an adequate energy intake. Protein substitutes are often given little importance, yet their pharmacological actions and clinical benefit are pivotal when managing PKU.<\/jats:p>","DOI":"10.3390\/nu13020484","type":"journal-article","created":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T05:44:42Z","timestamp":1612244682000},"page":"484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Protein Substitutes in PKU; Their Historical Evolution"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2579-8699","authenticated-orcid":false,"given":"Anne","family":"Daly","sequence":"first","affiliation":[{"name":"Birmingham Women\u2019s and Children\u2019s Hospital, NHS Foundation Trust, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7654-3621","authenticated-orcid":false,"given":"Sharon","family":"Evans","sequence":"additional","affiliation":[{"name":"Birmingham Women\u2019s and Children\u2019s Hospital, NHS Foundation Trust, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Pinto","sequence":"additional","affiliation":[{"name":"Birmingham Women\u2019s and Children\u2019s Hospital, NHS Foundation Trust, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Ashmore","sequence":"additional","affiliation":[{"name":"Birmingham Women\u2019s and Children\u2019s Hospital, NHS Foundation Trust, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Birmingham Women\u2019s and Children\u2019s Hospital, NHS Foundation Trust, Birmingham B4 6NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,2]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1515\/bchm2.1934.227.1-4.169","article-title":"Uber Ausscheidung von Phenylbrenztraubens\u00e4ure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillit\u00e4t","volume":"227","year":"1934","journal-title":"Z. 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