Physiological roles of the pantothenate kinases

Dansie, Lorraine E.; Reeves, Stacy A.; Miller, Karen K.; Zano, Stephen P.; Frank, Matthew W.; Pate, Caroline; Wang, Jina; Jackowski, Suzanne

doi:10.1042/bst20140096

Cited by 66 publications

(75 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The total PanK activity is a function of the Pank gene expression profile, which is different for each tissue. Furthermore, the total PanK activity and the CoA levels in a given tissue correlate with the relative abundance of Pank1 transcripts compared to the other Pank isoforms (44). Consistent with the correlation, Pank1 is a minor isoform in skeletal muscle while it is the major isoform in the heart, thus explaining the differences in the measured basal activities in these tissues from control animals.…”

Section: Resultsmentioning

confidence: 99%

Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2

Corbin

Rehg

Shepherd

et al. 2017

Molecular Genetics and Metabolism

Self Cite

View full text Add to dashboard Cite

Coenzyme A (CoA) is a cofactor that is central to energy metabolism and CoA synthesis is controlled by the enzyme pantothenate kinase (PanK). A transgenic mouse strain expressing human PANK2 was derived to determine the physiological impact of PANK overexpression and elevated CoA levels. The Tg(PANK2) mice expressed high levels of the transgene in skeletal muscle and heart; however, CoA was substantially elevated only in skeletal muscle, possibly associated with the comparatively low endogenous levels of acetyl-CoA, a potent feedback inhibitor of PANK2. Tg(PANK2) mice were smaller, had less skeletal muscle mass and displayed significantly impaired exercise tolerance and grip strength. Skeletal myofibers were characterized by centralized nuclei and aberrant mitochondria. Both the content of fully assembled complex I of the electron transport chain and ATP levels were reduced, while markers of oxidative stress were elevated in Tg(PANK2) skeletal muscle. These abnormalities were not detected in the Tg(PANK2) heart muscle, with the exception of spotty loss of cristae organization in the mitochondria. The data demonstrate that excessively high CoA may be detrimental to skeletal muscle function.

show abstract

Section: Resultsmentioning

confidence: 99%

Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2

Corbin

Rehg

Shepherd

et al. 2017

Molecular Genetics and Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…These results suggest that the increase in kidney CoA levels that occurs upon fasting may be promoted more by activation of the CoA biosynthetic pathway than by a decrease in CoA degradation. The flux through the CoA biosynthetic pathway is controlled by the pantothenate kinase (PanK) isoforms, and PanK1, which is the isoform that drives the increase in CoA levels observed in the liver of fasted mice, is also the major PanK isoform in the kidneys (13,48). Upon refeeding, a net decrease in CoA levels requires not only inhibition of CoA synthesis, but also active degradation of the cofactor accumulated in the fasted state.…”

Section: Discussionmentioning

confidence: 99%

Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform

Shumar

Kerr

Geldenhuys

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The four human and mouse PanK isoforms share a homologous carboxy-terminal catalytic domain, but differ in their amino-termini which direct the isoforms to different cellular compartments [8]. All cell types studied to date express several PanK isoforms [9] providing some degree of functional redundancy. The global chemical inhibition of CoA synthesis at the PanK step in mice results in a severe phenotype that leads to death [4].…”

Section: Introductionmentioning

confidence: 99%

“…The roles of individual PanKs were explored by creating global deletions of the Pank1 , Pank2 and Pank3 genes in mice [10]. Pank1 is highly expressed in liver [9], and the Pank1 −/− mice have reduced hepatic CoA content and exhibit fasting hypoglycemia and steatosis [11]. The murine Pank2 gene is highly expressed in testes [12], and Pank2 −/− mice exhibit azoospermia [13].…”

Section: Introductionmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Physiological roles of the pantothenate kinases

Cited by 66 publications

References 10 publications

Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2

Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2

Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform

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

Contact Info

Product

Resources

About