Modulation of Pantothenate Kinase 3 Activity by Small Molecules that Interact with the Substrate/Allosteric Regulatory Domain

Leonardi, Roberta; Zhang, Yongmei; Yun, Mi‐Kyung; Zhou, Ruobing; Zeng, Fu-Yue; Lin, Wenwei; Cui, Jimmy; Chen, Taosheng; Rock, Charles O.; White, Stephen W.; Jackowski, Suzanne

doi:10.1016/j.chembiol.2010.06.006

Cited by 47 publications

(56 citation statements)

References 35 publications

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“…Acyl-carnitines are an established activating ligand (8), and other signaling molecules like the N-acylethanolamines (7) may also play a role. We have previously demonstrated that small molecule effectors can modulate the activity of PANK3 in a manner that appears to be allosteric in nature (7,30). The studies reported here have confirmed the allosteric nature of PANK3 and now provide the framework for a structurebased optimization of these small molecule modulators of pantothenate kinase with potential therapeutic applications.…”

Section: Discussionsupporting

confidence: 54%

“…A predictive model of the closed active conformation of substrate-bound PANK3 suggested how the ATP and the pantothenate might be aligned for transfer of the ␥-phosphate with Glu-138 acting as the general base (7).…”

Section: Resultsmentioning

confidence: 99%

“…All pantothenate kinases operate by a compulsory ordered mechanism with ATP⅐Mg 2ϩ as the leading substrate followed by pantothenate ( Fig. 1) (7). The principal mechanism for controlling mammalian pantothenate kinase activity is through feedback inhibition by acetyl-CoA, and the isoforms differ in their sensitivity to this regulator ( Fig.…”

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confidence: 99%

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Allosteric Regulation of Mammalian Pantothenate Kinase

Subramanian

Yun²,

Yao

et al. 2016

Journal of Biological Chemistry

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Pantothenate kinase catalyzes the key regulatory step in CoA biosynthesis in bacteria and mammals (1-3). In mammals, there are four distinct kinases that exhibit tissue-specific expression as follows: PANK1␣ and PANK1␤ are splice variants of the PANK1 gene, and PANK2 and PANK3 are encoded by the PANK2 and PANK3 genes, respectively (4, 5). The kinase isoforms possess almost identical catalytic cores but differ in their amino termini that direct the enzymes to different subcellular compartments (6). Isoform 1␣ is targeted to the nucleus, whereas isoform 1␤ is associated with endosomes in humans and mice. Isoform 2 of mice is cytosolic, but the PANK2 gene in humans encodes a protein with both nuclear localization and mitochondrial targeting sequences. Isoform 3 is cytosolic in both species. All pantothenate kinases operate by a compulsory ordered mechanism with ATP⅐Mg 2ϩ as the leading substrate followed by pantothenate ( Fig. 1) (7). The principal mechanism for controlling mammalian pantothenate kinase activity is through feedback inhibition by acetyl-CoA, and the isoforms differ in their sensitivity to this regulator ( Fig. 1) (4, 8, 9). The 1␣ and 1␤ isoforms are least sensitive to inhibition, whereas isoforms 2 and 3 are more potently inhibited by acetyl-CoA. Acetyl-CoA inhibition is competitive with ATP⅐Mg 2ϩ , but acetyl-CoA binds far more tightly than ATP (10). Acyl-carnitines antagonize the inhibition of pantothenate kinases by acetyl-CoA (8).The importance of pantothenate kinase to mammalian physiology is highlighted by the phenotypes of knock-out mice and their connection to human disease. Isoform 1 is most highly expressed in the liver, and Pank1 Ϫ/Ϫ mice have lower total hepatic CoA and exhibit fatty acid ␤-oxidation and glucose homeostasis defects in the fasted state (11). In addition, Pank1 Ϫ/Ϫ Lep Ϫ/Ϫ mice have dramatically lower blood glucose and insulin levels compared with their diabetic Lep Ϫ/Ϫ counterparts, which highlights the connection between isoform 1 and glucose homeostasis (12). Consistent with this, an association between polymorphisms in the PANK1 gene and insulin levels was uncovered in a cohort of individuals in Finland (13). It has also been shown that the severe neurodegenerative disease pantothenate kinase-associated neurodegeneration arises from mutations in the human PANK2 gene (14). Unfortunately, Pank2 Ϫ/Ϫ mice do not recapitulate the pantothenate kinaseassociated neurodegeneration disease phenotype (15,16), and this may be due either to differences in the levels of isoform expression in mouse and human brains or to the fact that human PANK2 accumulates in the intra-membrane space in mitochondria, whereas mouse isoform 2 is cytosolic (9). Finally, Pank1 Ϫ/Ϫ Pank2 Ϫ/Ϫ double knock-out mice are unable to metabolize fats and ketones resulting in early postnatal death (16), and Pank1 Ϫ/Ϫ Pank3 Ϫ/Ϫ and Pank2 Ϫ/Ϫ Pank3 Ϫ/Ϫ double knock-out mice are both embryonic lethal. A chemical knockout of all pantothenate kinases in adult mice resulted in an 80% reduction in hepatic CoA levels a...

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Section: Discussionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

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Allosteric Regulation of Mammalian Pantothenate Kinase

Subramanian

Yun²,

Yao

et al. 2016

Journal of Biological Chemistry

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“…Sel1L, regulates self-fate decisions [44] and enhances tumor progression [45] was expressed over 3 fold more in Oct4/GFP cells than the Nestin/GFP cells (Figure 3H). UBE2q1 and Pank3 are regulators of cellular metabolism and enhance cell growth [46,47] were also confirmed to have a greater than 3 fold higher expression in the Oct4/GFP cells compared to Nestin/GFP cells (Figure 3H).…”

Section: Resultsmentioning

confidence: 93%

Small molecule antagonist of the bone morphogenetic protein type I receptors suppresses growth and expression of Id1 and Id3 in lung cancer cells expressing Oct4 or nestin

et al. 2013

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BackgroundBone morphogenetic proteins (BMP) are embryonic morphogens that are aberrantly expressed in lung cancer. BMPs mediate cell fate decisions and self-renewal of stem cells, through transcription regulation of inhibitor of differentiation protein/DNA binding proteins (Id1-3). Inhibition of BMP signaling decreases growth and induces cell death of lung cancer cells lines by downregulating the expression of Id proteins. It is not known whether the BMP signaling cascade regulates growth and the expression of Id proteins of lung cancer cells expressing the stem cell markers Oct4 and/or nestin.MethodsLung cancer cells expressing Oct4 or nestin were isolated from lung cancer cell lines by stably transfecting the Oct4 promoter or nestin promoter expression vectors that induce expression of the green fluorescent protein reporter.ResultsOur studies suggest that lung cancer cells expressing Oct4 or nestin are different cell populations. Microarray and quantitative RT-PCR demonstrated that the expression of specific stem cell markers were different between isolated Oct4 and nestin cells. Both the Oct4 and nestin populations were more tumorigenic than controls but histologically they were quite different. The isolated Oct4 and nestin cells also responded differently to inhibition of BMP signaling. Blockade of BMP signaling with the BMP receptor antagonist DMH2 caused significant growth inhibition of both the Oct4 and nestin cell populations but only increased cell death in the nestin population. DMH2 also induced the expression of nestin in the Oct4 population but not in the nestin cells. We also show that BMP signaling is an important regulator of Id1 and Id3 in both the Oct4 and nestin cell populations. Furthermore, we show that NeuN is frequently expressed in NSCLC and provide evidence suggesting that Oct4 cells give rise to cancer cells expressing nestin and/or NeuN.ConclusionThese studies show that although biologically different, BMP signaling is growth promoting in cancer cells expressing Oct4 or nestin. Inhibition of BMP signaling decreases expression of Id proteins and suppresses growth of cancer cells expressing Oct4 or Nestin. Small molecule antagonists of the BMP type I receptors represent potential novel drugs to target the population of cancer cells expressing stem cell markers.

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“…Alternatively, it may be related to drug therapy; for example, the tamoxifen that most breast cancer patients receive. Tamoxifen was shown to modulate the activity of the pantothenate kinase isoform PANK 2 (Leonardi et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Radiation-induced Changes in Levels of Selected Proteins in Peripheral Blood Serum of Breast Cancer Patients as a Potential Triage Biodosimeter for Large-scale Radiological Emergencies

Deperas‐Kaminska¹,

Bajinskis²,

Marczyk³

et al. 2014

Health Physics

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The threat of a large scale radiological emergency, where thousands of people may require fast biological dosimetry for the purpose of triage, makes it necessary to search for new, high throughput biological dosimeters. The authors tested an assay based on the quantitative analysis of selected proteins in peripheral blood serum. They were particularly interested in testing proteins that are specific to irradiation of skin, as these can be used in cases of partial body exposure. Candidate proteins were identified in an earlier study with mice, where skin of the animals was exposed to different doses of radiation and global expression of serum proteins was analyzed. Eight proteins were found, the expression of which showed a consistent dose-response relationship. Human analogues of these proteins were identified, and their expression was measured in peripheral blood serum of 16 breast cancer patients undergoing external beam radiotherapy. The proteins were Apolipoprotein E; Apolipoprotein H; Complement protein 7; Prothrombinase; Pantothenate Kinase 4; Alpha-2-macroglobulin; Fetuin B and Alpha-1-Anti-Chymotrypsin. Measurements were carried out in blood samples collected prior to exposure (control), on the day after one fraction (2 Gy), on the day after five fractions (10 Gy), on the day after 10 fractions (20 Gy), and 1 mo after 23-25 fractions (total dose of 46-50 Gy). Multivariate analysis was carried out, and a multinomial logistic regression model was built. The results indicate that the combined analysis of Apolipoprotein E, Factor X, and Pantothenate Kinase 4 allows discriminating between exposure to 2 Gy and lower and between 10 Gy and higher. The discrimination is possible up to 1 mo after exposure.

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Modulation of Pantothenate Kinase 3 Activity by Small Molecules that Interact with the Substrate/Allosteric Regulatory Domain

Cited by 47 publications

References 35 publications

Allosteric Regulation of Mammalian Pantothenate Kinase

Allosteric Regulation of Mammalian Pantothenate Kinase

Small molecule antagonist of the bone morphogenetic protein type I receptors suppresses growth and expression of Id1 and Id3 in lung cancer cells expressing Oct4 or nestin

Radiation-induced Changes in Levels of Selected Proteins in Peripheral Blood Serum of Breast Cancer Patients as a Potential Triage Biodosimeter for Large-scale Radiological Emergencies

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