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However, the precise mechanistic details of how acetylation converts leucine into a drug are unknown. Here we show that acetylation of leucine switches its uptake into cells from the\n                    <jats:sc>l<\/jats:sc>\n                    -type amino acid transporter (LAT1) used by leucine to organic anion transporters (OAT1 and OAT3) and the monocarboxylate transporter type 1 (MCT1). Both the kinetics of MCT1 (lower affinity compared to LAT1) and the ubiquitous tissue expression of MCT1 make it well suited for uptake and distribution of\n                    <jats:italic>N<\/jats:italic>\n                    -acetyl-\n                    <jats:sc>l<\/jats:sc>\n                    -leucine. MCT1-mediated uptake of a\n                    <jats:italic>N<\/jats:italic>\n                    -acetyl-\n                    <jats:sc>l<\/jats:sc>\n                    -leucine as a prodrug of leucine bypasses LAT1, the rate-limiting step in activation of leucine-mediated signalling and metabolic process inside cells such as mTOR. Converting an amino acid into an anion through acetylation reveals a way for the rational design of drugs to target anion transporters.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-95255-5","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T06:04:26Z","timestamp":1628057066000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Acetylation turns leucine into a drug by membrane transporter switching"],"prefix":"10.1038","volume":"11","author":[{"given":"Grant C.","family":"Churchill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Strupp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cailley","family":"Factor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Bremova-Ertl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mallory","family":"Factor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc C.","family":"Patterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances M.","family":"Platt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antony","family":"Galione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"95255_CR1","first-page":"15","volume":"141","author":"E Neuzil","year":"2002","unstructured":"Neuzil, E., Ravaine, S. & Cousse, H. 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He has received speaker\u2019s honoraria from Abbott, Actelion, Auris Medical, Biogen, Eisai, Gr\u00fcnenthal, GSK, Henning Pharma, Interacoustics, Merck, MSD, Otometrics, Pierre-Fabre, TEVA, UCB. He is a shareholder of IntraBio. He acts as a consultant for Abbott, Actelion, AurisMedical, Heel, IntraBio and Sensorion. MF is a co-founder, shareholder, and Chairman of IntraBio. MP is a shareholder of IntraBio and has received consulting fees, honoraria, and research grants from Actelion Pharmaceuticals Ltd. and Biomarin. TBE received honoraria for lecturing from Actelion and Sanofi Genzyme. CF is a consultant to IntraBio. GCC, AG and FP are cofounders, shareholders and consultants to IntraBio. IntraBio Ltd is the applicant for patents WO2018229738 (Treatment For Migraine), WO2017182802 (Acetyl-Leucine Or A Pharmaceutically Acceptable Salt Thereof For Improved Mobility And Cognitive Function), WO2019078915 and WO2018029658 (Therapeutic Agents For Neurodegenerative Diseases), WO2018029657 (Pharmaceutical Compositions And Uses Directed To Lysosomal Storage Disorders), and WO2019079536 (Therapeutic Agents For Improved Mobility And Cognitive Function And For Treating Neurodegenerative Diseases And Lysosomal Storage Disorders).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15812"}}