{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:27:20Z","timestamp":1792675640927,"version":"4.5.0"},"reference-count":56,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T00:00:00Z","timestamp":1540252800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T00:00:00Z","timestamp":1540252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human\n                    <jats:italic>PANK<\/jats:italic>\n                    genes, and inactivating mutations in\n                    <jats:italic>PANK2<\/jats:italic>\n                    lead to pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the pantothenate pocket and engages the dimer interface to form a PANK\u2022ATP\u2022Mg\n                    <jats:sup>2+<\/jats:sup>\n                    \u2022PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.\n                  <\/jats:p>","DOI":"10.1038\/s41467-018-06703-2","type":"journal-article","created":{"date-parts":[[2018,10,17]],"date-time":"2018-10-17T05:29:05Z","timestamp":1539754145000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["A therapeutic approach to pantothenate kinase associated neurodegeneration"],"prefix":"10.1038","volume":"9","author":[{"given":"Lalit Kumar","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chitra","family":"Subramanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Kyung","family":"Yun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Frank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8188-5944","authenticated-orcid":false,"given":"Stephen W.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8648-4189","authenticated-orcid":false,"given":"Charles O.","family":"Rock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2397-0443","authenticated-orcid":false,"given":"Richard E.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6855-1429","authenticated-orcid":false,"given":"Suzanne","family":"Jackowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,10,23]]},"reference":[{"key":"6703_CR1","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/ng572","volume":"28","author":"B Zhou","year":"2001","unstructured":"Zhou, B. et al. 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L.K.S., C.S., M.-K.Y., C.O.R., R.E.L. and S.J. are inventors on a pending patent application (PCT\/US17\/39037) \u201cSmall molecule modulators of pantothenate kinases\u201d held by St. Jude Children\u2019s Research Hospital that covers the pantazine chemical series disclosed in this manuscript. S.J., R.E.L., C.O.R. and S.W.W. received research funding from CoA Ttherapeutics. The authors declare no other competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4399"}}