Extracellular 4′-phosphopantetheine is a source for intracellular coenzyme A synthesis

Srinivasan, Balaji; Baratashvili, Madina; Zwaag, Marianne van der; Kanon, Bart; Colombelli, Cristina; Lambrechts, Roald A.; Schaap, Onno; Nollen, Ellen A. A.; Podgoršek, Ajda; Kosec, Gregor; Petković, Hrvoje; Hayflick, Susan J.; Tiranti, Valeria; Reijngoud, Dirk-Jan; Grzeschik, Nicola A.; Sibon, Ody C. M.

doi:10.1038/nchembio.1906

Cited by 107 publications

(163 citation statements)

References 47 publications

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“…These include aryloxy amino acid amidates, cyclic phosphoramidates, phosphorodiamidates, cyclic esters ( cyclo Sal), cyclic disulfides, S-acyl-2-thioethyl phosphotriesters, pivaloyloxymethyl esters (POM), protection by attachment to lipids, and many other options [21–24,26,30–35]. An interesting alternate option may be treatment with phosphopantetheine, which rescues Drosophila cells deficient in CoA by bypassing PanK [36]. Each of these protection technologies have their strengths and weaknesses with respect to bioavailability and stability in mammals that will need to be evaluated to optimize the tissue penetration and plasma stability characteristics to create a Ppan prodrug with the potential to treat PKAN disease.…”

Section: Discussionmentioning

confidence: 99%

Correction of a genetic deficiency in pantothenate kinase 1 using phosphopantothenate replacement therapy

Zano

Pate

Frank

et al. 2015

Molecular Genetics and Metabolism

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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 tripleisotopically 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.

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Section: Discussionmentioning

confidence: 99%

Correction of a genetic deficiency in pantothenate kinase 1 using phosphopantothenate replacement therapy

Zano

Pate

Frank

et al. 2015

Molecular Genetics and Metabolism

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“…CoA is produced in the cytosol and subsequently actively transported into the mitochondrial matrix. Alternatively, can access CoA from the extracellular environment thanks to the action of extracellular ectonucleotide pyrophosphatases contained in the serum 70 . These enzymes cleave the CoA molecule to form 4’-phosphopantetheine, which can enter the cells one enzymatic step above CoA formation by COASY…”

Section: Resultsmentioning

confidence: 99%

A framework for large-scale metabolome drug profiling links coenzyme A metabolism to the toxicity of anti-cancer drug dichloroacetate

2018

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Metabolic profiling of cell line collections has become an invaluable tool to study disease etiology, drug modes of action and to select personalized treatments. However, large-scale in vitro dynamic metabolic profiling is limited by time-consuming sampling and complex measurement procedures. By adapting a mass spectrometry-based metabolomics workflow for high-throughput profiling of diverse adherent mammalian cells, we establish a framework for the rapid measurement and analysis of drug-induced dynamic changes in intracellular metabolites. This methodology is scalable to large compound libraries and is here applied to study the mechanism underlying the toxic effect of dichloroacetate in ovarian cancer cell lines. System-level analysis of the metabolic responses revealed a key and unexpected role of CoA biosynthesis in dichloroacetate toxicity and the more general importance of CoA homeostasis across diverse human cell lines. The herein-proposed strategy for high-content drug metabolic profiling is complementary to other molecular profiling techniques, opening new scientific and drug-discovery opportunities.

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“…Eukaryotic cells readily take up and transform the CoA precursor 4′-phosphopantetheine [52] into CoA. In the case of P. falciparum , this task is made more difficult by the fact that the parasite is surrounded by the outer RBC membrane and the parasitophorous vacuole membrane.…”

Section: Discussionmentioning

confidence: 99%

Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway

et al. 2016

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BackgroundIn the fight against malaria, the discovery of chemical compounds with a novel mode of action and/or chemistry distinct from currently used drugs is vital to counteract the parasite’s known ability to develop drug resistance. Another desirable aspect is efficacy against gametocytes, the sexual developmental stage of the parasite which enables the transmission through Anopheles vectors. Using a chemical rescue approach, we previously identified compounds targeting Plasmodium falciparum coenzyme A (CoA) synthesis or utilization, a promising target that has not yet been exploited in anti-malarial drug development.ResultsWe report on the outcomes of a series of biological tests that help to define the species- and stage-specificity, as well as the potential targets of these chemically diverse compounds. Compound activity against P. falciparum gametocytes was determined to assess stage-specificity and transmission-reducing potential. Against early stage gametocytes IC50 values ranging between 60 nM and 7.5 μM were obtained. With the exception of two compounds with sub-micromolar potencies across all intra-erythrocytic stages, activity against late stage gametocytes was lower. None of the compounds were specific pantothenate kinase inhibitors. Chemical rescue profiling with CoA pathway intermediates demonstrated that most compounds acted on either of the two final P. falciparum CoA synthesis enzymes, phosphopantetheine adenylyltransferase (PPAT) or dephospho CoA kinase (DPCK). The most active compound targeted either phosphopantothenoylcysteine synthetase (PPCS) or phosphopantothenoylcysteine decarboxylase (PPCDC). Species-specificity was evaluated against Trypanosoma cruzi and Trypanosoma brucei brucei. No specific activity against T. cruzi amastigotes was observed; however three compounds inhibited the viability of trypomastigotes with sub-micromolar potencies and were confirmed to act on T. b. brucei CoA synthesis. ConclusionsUtilizing the compounds we previously identified as effective against asexual P. falciparum, we demonstrate for the first time that gametocytes, like the asexual stages, depend on CoA, with two compounds exhibiting sub-micromolar potencies across asexual forms and all gametocytes stages tested. Furthermore, three compounds inhibited the viability of T. cruzi and T. b. brucei trypomastigotes with sub-micromolar potencies and were confirmed to act on T. b. brucei CoA synthesis, indicating that the CoA synthesis pathway might represent a valuable new drug target in these parasite species.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1860-3) contains supplementary material, which is available to authorized users.

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Extracellular 4′-phosphopantetheine is a source for intracellular coenzyme A synthesis

Cited by 107 publications

References 47 publications

Correction of a genetic deficiency in pantothenate kinase 1 using phosphopantothenate replacement therapy

Correction of a genetic deficiency in pantothenate kinase 1 using phosphopantothenate replacement therapy

A framework for large-scale metabolome drug profiling links coenzyme A metabolism to the toxicity of anti-cancer drug dichloroacetate

Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway

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