{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T10:07:15Z","timestamp":1781086035085,"version":"3.54.1"},"reference-count":37,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"FWF Austrian Science Fund","doi-asserted-by":"publisher","award":["I525, I1593, P22276, P19060 and W1221"],"award-info":[{"award-number":["I525, I1593, P22276, P19060 and W1221"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Commission\u2019s Seventh Framework Program","award":["277984"],"award-info":[{"award-number":["277984"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive neurodegenerative disease caused by mutations in the pantothenate kinase 2 (PANK2) gene and associated with iron deposition in basal ganglia. Pantothenate kinase isoforms catalyze the first step in coenzyme A (CoA) biosynthesis. Since PANK2 is the only isoform in erythrocytes, these cells are an excellent ex vivo model to study the effect of PANK2 point mutations on expression\/stability and activity of the protein as well as on the downstream molecular consequences. PKAN erythrocytes containing the T528M PANK2 mutant had residual enzyme activities but variable PANK2 abundances indicating an impaired regulation of the protein. Patients with G521R\/G521R, G521R\/G262R, and R264N\/L275fs PANK2 mutants had no residual enzyme activity and strongly reduced PANK2 abundance. G521R inactivates the catalytic activity of the enzyme, whereas G262R and the R264N point mutations impair the switch from the inactive to the active conformation of the PANK2 dimer. Metabolites in cytosolic extracts were analyzed by gas chromatography\u2013mass spectrometry and multivariate analytic methods revealing changes in the carboxylate metabolism of erythrocytes from PKAN patients as compared to that of the carrier and healthy control. Assuming low\/absent CoA levels in PKAN erythrocytes, changes are consistent with a model of altered citrate channeling where citrate is preferentially converted to \u03b1-ketoglutarate and \u03b1-hydroxyglutarate instead of being used for de novo acetyl-CoA generation. This finding hints at the importance of carboxylate metabolism in PKAN pathology with potential links to reduced cytoplasmic acetyl-CoA levels in neurons and to aberrant brain iron regulation.<\/jats:p>","DOI":"10.3390\/biom12020325","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T08:14:46Z","timestamp":1645431286000},"page":"325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Potential Citrate Shunt in Erythrocytes of PKAN Patients Caused by Mutations in Pantothenate Kinase 2"],"prefix":"10.3390","volume":"12","author":[{"given":"Maike","family":"Werning","sequence":"first","affiliation":[{"name":"Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Dobretzberger","sequence":"additional","affiliation":[{"name":"Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Brenner","sequence":"additional","affiliation":[{"name":"Molecular Systems Biology (MOSYS), University of Vienna, 1010 Vienna, Austria"},{"name":"Department of Pharmaceutical Sciences\/Pharmacognosy, Faculty of Life Sciences, University of Vienna, 1010 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernst W.","family":"M\u00fcllner","sequence":"additional","affiliation":[{"name":"Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1454-4044","authenticated-orcid":false,"given":"Georg","family":"Mlynek","sequence":"additional","affiliation":[{"name":"Max Perutz Labs, Department of Structural and Computational Biology, University of Vienna, 1010 Vienna, Austria"},{"name":"Core Facility Biomolecular and Cellular Analysis, University of Natural Resources and Life Sciences, 1190 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0252-2972","authenticated-orcid":false,"given":"Kristina","family":"Djinovic-Carugo","sequence":"additional","affiliation":[{"name":"Max Perutz Labs, Department of Structural and Computational Biology, University of Vienna, 1010 Vienna, Austria"},{"name":"Department of Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Baron","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Fragner","sequence":"additional","affiliation":[{"name":"Molecular Systems Biology (MOSYS), University of Vienna, 1010 Vienna, Austria"},{"name":"Vienna Metabolomics Center (VIME), University of Vienna, 1010 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almut T.","family":"Bischoff","sequence":"additional","affiliation":[{"name":"Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University (LMU Klinikum), 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1241-3684","authenticated-orcid":false,"given":"Boriana","family":"B\u00fcchner","sequence":"additional","affiliation":[{"name":"Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University (LMU Klinikum), 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[{"name":"Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University (LMU Klinikum), 80336 Munich, Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfram","family":"Weckwerth","sequence":"additional","affiliation":[{"name":"Molecular Systems Biology (MOSYS), University of Vienna, 1010 Vienna, Austria"},{"name":"Vienna Metabolomics Center (VIME), University of Vienna, 1010 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Salzer","sequence":"additional","affiliation":[{"name":"Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/ng572","article-title":"A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome","volume":"28","author":"Zhou","year":"2001","journal-title":"Nat. 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