Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency

Ivano Di Meo; Cristina Colombelli; Balaji Srinivasan; Marianne De Villiers; Jeffrey Hamada; Suh Y. Jeong; Rachel Fox; Randall L. Woltjer; Pieter G. Tepper; Liza L. Lahaye; Emanuela Rizzetto; Clara H. Harrs; Theo De Boer; Marianne Van Der Zwaag; Branko Jenko; Alen Čusak; Jerca Pahor; Gregor Kosec; Nicola A. Grzeschik; Susan J. Hayflick; Valeria Tiranti; Ody C.M. Sibon

doi:10.1038/s41598-017-11564-8

Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency

Ivano Di Meo, Cristina Colombelli, Balaji Srinivasan, Marianne De Villiers, Jeffrey Hamada, Suh Y. Jeong, Rachel Fox, Randall L. Woltjer, Pieter G. Tepper, Liza L. Lahaye, Emanuela Rizzetto, Clara H. Harrs, Theo De Boer, Marianne Van Der Zwaag, Branko Jenko, Alen Čusak, Jerca Pahor, Gregor Kosec, Nicola A. Grzeschik, Susan J. HayflickValeria Tiranti, Ody C.M. Sibon

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Abstract

Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4′-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.

Original language	English (US)
Article number	11260
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-11564-8
State	Published - Dec 1 2017

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Di Meo, I., Colombelli, C., Srinivasan, B., De Villiers, M., Hamada, J., Jeong, S. Y., Fox, R., Woltjer, R. L., Tepper, P. G., Lahaye, L. L., Rizzetto, E., Harrs, C. H., De Boer, T., Van Der Zwaag, M., Jenko, B., Čusak, A., Pahor, J., Kosec, G., Grzeschik, N. A., ... Sibon, O. C. M. (2017). Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency. Scientific Reports, 7(1), Article 11260. https://doi.org/10.1038/s41598-017-11564-8

Di Meo, I, Colombelli, C, Srinivasan, B, De Villiers, M, Hamada, J, Jeong, SY, Fox, R, Woltjer, RL, Tepper, PG, Lahaye, LL, Rizzetto, E, Harrs, CH, De Boer, T, Van Der Zwaag, M, Jenko, B, Čusak, A, Pahor, J, Kosec, G, Grzeschik, NA, Hayflick, SJ, Tiranti, V & Sibon, OCM 2017, 'Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency', Scientific Reports, vol. 7, no. 1, 11260. https://doi.org/10.1038/s41598-017-11564-8

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title = "Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency",

abstract = "Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4′-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.",

author = "{Di Meo}, Ivano and Cristina Colombelli and Balaji Srinivasan and {De Villiers}, Marianne and Jeffrey Hamada and Jeong, {Suh Y.} and Rachel Fox and Woltjer, {Randall L.} and Tepper, {Pieter G.} and Lahaye, {Liza L.} and Emanuela Rizzetto and Harrs, {Clara H.} and {De Boer}, Theo and {Van Der Zwaag}, Marianne and Branko Jenko and Alen {\v C}usak and Jerca Pahor and Gregor Kosec and Grzeschik, {Nicola A.} and Hayflick, {Susan J.} and Valeria Tiranti and Sibon, {Ody C.M.}",

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AU - Di Meo, Ivano

AU - Colombelli, Cristina

AU - Srinivasan, Balaji

AU - De Villiers, Marianne

AU - Hamada, Jeffrey

AU - Jeong, Suh Y.

AU - Fox, Rachel

AU - Woltjer, Randall L.

AU - Tepper, Pieter G.

AU - Lahaye, Liza L.

AU - Rizzetto, Emanuela

AU - Harrs, Clara H.

AU - De Boer, Theo

AU - Van Der Zwaag, Marianne

AU - Jenko, Branko

AU - Čusak, Alen

AU - Pahor, Jerca

AU - Kosec, Gregor

AU - Grzeschik, Nicola A.

AU - Hayflick, Susan J.

AU - Tiranti, Valeria

AU - Sibon, Ody C.M.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4′-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.

AB - Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4′-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.

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Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency

Abstract

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