Abstract
In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients. Fosmetpantotenate restored coenzyme A in short-hairpin RNA pantothenate kinase 2 gene-silenced neuroblastoma cells and was permeable in a blood-brain barrier model. The rate of fosmetpantotenate metabolism in blood is species-dependent. Following up to 700 mg/kg orally, blood exposure to fosmetpantotenate was negligible in rat and mouse, but measurable in monkey. Consistent with the difference in whole blood half-life, fosmetpantotenate dosed orally was found in the brains of the monkey (striatal dialysate) but was absent in mice. Following administration of isotopically labeled-fosmetpantotenate to mice, ~40% of liver coenzyme A (after 500 mg/kg orally) and ~50% of brain coenzyme A (after 125 μg intrastriatally) originated from isotopically labeled-fosmetpantotenate. Additionally, 10-day dosing of isotopically labeled-fosmetpantotenate, 12.5 μg, intracerebroventricularly in mice led to ~30% of brain coenzyme A containing the stable isotopic labels. This work supports the hypothesis that fosmetpantotenate acts to replace reduced phosphopantothenic acid in pantothenate kinase 2-deficient tissues.
Highlights
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive neurodegenerative disease [1,2,3] caused by a mutation in the pantothenate kinase-2 (PANK2) gene on chromosome 20p13
In vitro effects of fosmetpantotenate following incubations in short-hairpin RNA (shRNA) PanK2 knocked down human neuroblastoma cells
Our initial experiments were designed to characterize the effects of fosmetpantotenate on shRNA PanK2 knocked down cells
Summary
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive neurodegenerative disease [1,2,3] caused by a mutation in the pantothenate kinase-2 (PANK2) gene on chromosome 20p13. In PKAN, the mutation in the PANK2 gene, encoding the mitochondrial form of pantothenate kinase (PanK), causes a reduction in the activity of the PanK2 enzyme, which converts pantothenate (PA, vitamin B5) to phosphopantothenate (PPA), in the biosynthetic pathway to coenzyme A (CoA) [11]. It has been postulated that the defective PanK2 enzyme, localized primarily in mitochondria [1], has decreased ability to phosphorylate pantothenate, leading to decreased concentrations of CoA in vulnerable tissues, including brain. CoA and its acetylated metabolite, acetyl-CoA, are key factors in several cellular processes, including energy metabolism, autophagy, and mitosis, acting as a central metabolic intermediate and as signal transducers in anabolic and catabolic reactions [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
