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
Article number	11260
Number of pages	12
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-11564-8
Publication status	Published - 12-Sept-2017

Keywords

BRAIN IRON ACCUMULATION
COENZYME-A
ESCHERICHIA-COLI
PHOSPHOPANTOTHENOYLCYSTEINE SYNTHETASE
PANTETHINE RESCUES
COA SYNTHASE
NEURODEGENERATION
DROSOPHILA
IDENTIFICATION
BIOSYNTHESIS

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Acetyl-4′-phosphopantetheine is stable in serumFinal publisher's version, 3.93 MBLicence: CC BY

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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

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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.",

keywords = "BRAIN IRON ACCUMULATION, COENZYME-A, ESCHERICHIA-COLI, PHOSPHOPANTOTHENOYLCYSTEINE SYNTHETASE, PANTETHINE RESCUES, COA SYNTHASE, NEURODEGENERATION, DROSOPHILA, IDENTIFICATION, BIOSYNTHESIS",

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}",

year = "2017",

month = sep,

day = "12",

doi = "10.1038/s41598-017-11564-8",

language = "English",

volume = "7",

journal = "Scientific Reports",

issn = "2045-2322",

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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

TY - JOUR

T1 - Acetyl-4'-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency

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 - 2017/9/12

Y1 - 2017/9/12

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.

KW - BRAIN IRON ACCUMULATION

KW - COENZYME-A

KW - ESCHERICHIA-COLI

KW - PHOSPHOPANTOTHENOYLCYSTEINE SYNTHETASE

KW - PANTETHINE RESCUES

KW - COA SYNTHASE

KW - NEURODEGENERATION

KW - DROSOPHILA

KW - IDENTIFICATION

KW - BIOSYNTHESIS

U2 - 10.1038/s41598-017-11564-8

DO - 10.1038/s41598-017-11564-8

M3 - Article

C2 - 28900161

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 11260

ER -

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

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Keywords

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