title: Correction of a genetic deficiency in pantothenate kinase 1 using phosphopantothenate replacement therapy.
abstract: Coenzyme A (CoA) is a ubiquitous cofactor involved in numerous essential biochemical transformations, and along with its thioesters is a key regulator of intermediary metabolism. Pantothenate (vitamin B5) phosphorylation by pantothenate kinase (PanK) is thought to control the rate of CoA production. Pantothenate kinase associated neurodegeneration is a hereditary disease that arises from mutations that inactivate the human PANK2 gene. Aryl phosphoramidate phosphopantothenate derivatives were prepared to test the feasibility of using phosphopantothenate replacement therapy to bypass the genetic deficiency in the Pank1(-/-) mouse model. The efficacies of candidate compounds were first compared by measuring the ability to increase CoA levels in Pank1(-/-) mouse embryo fibroblasts. Administration of selected candidate compounds to Pank1(-/-) mice corrected their deficiency in hepatic CoA. The PanK bypass was confirmed by the incorporation of intact phosphopantothenate into CoA using triple-isotopically labeled compound. These results provide strong support for PanK as a master regulator of intracellular CoA and illustrate the feasibility of employing PanK bypass therapy to restore CoA levels in genetically deficient mice.
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Zano
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pate
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Frank
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.affiliation: St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: suzanne.jackowski@stjude.org.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D003065:Coenzyme A / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D006211:Pantothenate Kinase-Associated Neurodegeneration / Q000178:diet therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010205:Pantothenic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics; D061251:Primary Cell Culture
chemical_list: D000577:Amides; D010756:Phosphoric Acids; D010205:Pantothenic Acid; C011988:phosphopantothenic acid; C011067:phosphoramidic acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A
keywords: Coenzyme A; PKAN; Pantothenate kinase; Pantothenic acid