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pantothenate kinase

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https://www.readbyqxmd.com/read/29844889/pantothenate-kinase-associated-neurodegeneration-clinical-aspects-diagnosis-and-treatments
#1
Saeed Razmeh, Amir Hassan Habibi, Maryam Orooji, Elham Alizadeh, Karim Moradiankokhdan, Behroz Razmeh
Pantothenate Kinase-Associated Neurodegeneration (PKAN) is an autosomal recessive disorder characterized by a mutation in the PANK 2 gene. The clinical presentation may range from only speech disorder to severe generalized dystonia, spasticity, Visual loss, dysphagia and dementia. The hallmark of this disease is eyes of the tiger sign in the medial aspect of bilateral globus pallidus on T2-weighted MRI that is a hyperintense lesion surrounded by hypointensity. Common treatments for PKAN disease include anticholinergics, botulinum toxin, Oral and Intrathecal baclofen, Iron chelation drugs and surgical procedures such as ablative pallidotomy or thalamotomy, Deep brain stimulation...
March 30, 2018: Neurology International
https://www.readbyqxmd.com/read/29768338/botulinum-toxin-injection-to-improve-functional-independence-and-to-alleviate-parenting-stress-in-a-child-with-advanced-pantothenate-kinase-associated-neurodegeneration-a-case-report-and-literature-review
#2
REVIEW
Cho-I Lin, Kuan-Lin Chen, Ta-Shen Kuan, Sheng-Han Lin, Wei-Pin Lin, Yu-Ching Lin
RATIONALE: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disease. Progressive motor symptoms such as dystonia and spasticity begin in childhood and relentlessly become incapacitating later in life. Treatments including anticholinergics and iron chelation are usually ineffective. Botulinum toxin type A (BoNT-A) is effective for adult patients with dystonia or spasticity. PATIENT CONCERNS: We reported a 10-year-old female patient with advanced PKAN, manifesting as generalized dystonia and spasticity...
May 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29767814/inborn-errors-of-coenzyme-a-metabolism-and-neurodegeneration
#3
Ivano Di Meo, Miryam Carecchio, Valeria Tiranti
Two inborn errors of coenzyme A (CoA) metabolism are responsible for distinct forms of neurodegeneration with brain iron accumulation (NBIA), a heterogeneous group of neurodegenerative diseases having as a common denominator iron accumulation mainly in the inner portion of globus pallidus. Pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA and is caused by mutations in the pantothenate kinase 2 gene (PANK2), coding for a mitochondrial enzyme, which phosphorylates vitamin B5 in the first reaction of the CoA biosynthetic pathway...
May 16, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29765892/botulinum-toxin-a-injection-in-the-treatment-of-spasticity-in-a-infantile-onset-neurodegeneration-with-brain-iron-accumulation-a-case-report
#4
Hwan Kwon Do, Geun Yeol Jo, Jun Koo Kwon, Woo Jin Kim
Pantothenate kinase-associated neurodegeneration (PKAN) is a neurodegenerative disorder characterized by iron accumulation in the globus pallidus (GP) of the brain (neurodegeneration with brain iron accumulation [NBIA]), which is characterized by dystonia and spasticity resulting in postural difficulties. A 33-month-old boy was admitted with a pronounced gait disturbance. Marked hypertonicity in the patient's both calf muscles was noted, resulting in waddling with repeated slip-falls. NBIA was suspected by high T2 intensity in the GP on brain MRI, then it was confirmed by detecting PANK2 mutation...
April 2018: Annals of Rehabilitation Medicine
https://www.readbyqxmd.com/read/29619158/a-pilot-trial-of-deferiprone-in-pantothenate-kinase-associated-neurodegeneration-patients
#5
Mohammad Rohani, Saeed Razmeh, Gholam Ali Shahidi, Elham Alizadeh, Maryam Orooji
Pantothenate kinase-associated neurodegeneration (PKAN) is the most common form of neurodegeneration with brain iron accumulation, it is an autosomal recessive disease due to mutation in PANK 2 on chromosome 20, which causes the accumulation of iron in basal ganglia and production of free radicals that cause degeneration of the cells. Deferiprone is an iron chelator that was used in treatment of thalassemia patients, it can cross the blood-brain barrier and reverse the iron deposition in the brain. Five patients with genetically confirmed PKAN received 15 mg/kg deferiprone twice daily...
December 11, 2017: Neurology International
https://www.readbyqxmd.com/read/29614109/mutations-in-the-pantothenate-kinase-of-plasmodium-falciparum-confer-diverse-sensitivity-profiles-to-antiplasmodial-pantothenate-analogues
#6
Erick T Tjhin, Christina Spry, Alan L Sewell, Annabelle Hoegl, Leanne Barnard, Anna E Sexton, Ghizal Siddiqui, Vanessa M Howieson, Alexander G Maier, Darren J Creek, Erick Strauss, Rodolfo Marquez, Karine Auclair, Kevin J Saliba
The malaria-causing blood stage of Plasmodium falciparum requires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues...
April 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29522513/fosmetpantotenate-re-024-a-phosphopantothenate-replacement-therapy-for-pantothenate-kinase-associated-neurodegeneration-mechanism-of-action-and-efficacy-in-nonclinical-models
#7
Daniel Elbaum, Maria G Beconi, Edith Monteagudo, Annalise Di Marco, Maria S Quinton, Kathryn A Lyons, Andrew Vaino, Steven Harper
In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients...
2018: PloS One
https://www.readbyqxmd.com/read/29518650/characterization-and-validation-of-entamoeba-histolytica-pantothenate-kinase-as-a-novel-anti-amebic-drug-target
#8
Arif Nurkanto, Ghulam Jeelani, Takehiro Yamamoto, Yoshiko Naito, Takako Hishiki, Mihoko Mori, Makoto Suematsu, Kazuro Shiomi, Tetsuo Hashimoto, Tomoyoshi Nozaki
The Coenzyme A (CoA), as a cofactor involved in >100 metabolic reactions, is essential to the basic biochemistry of life. Here, we investigated the CoA biosynthetic pathway of Entamoeba histolytica (E. histolytica), an enteric protozoan parasite responsible for human amebiasis. We identified four key enzymes involved in the CoA pathway: pantothenate kinase (PanK, EC 2.7.1.33), bifunctional phosphopantothenate-cysteine ligase/decarboxylase (PPCS-PPCDC), phosphopantetheine adenylyltransferase (PPAT) and dephospho-CoA kinase (DPCK)...
April 2018: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/29453370/a-multitarget-approach-to-drug-discovery-inhibiting-mycobacterium-tuberculosis-pyrg-and-pank
#9
Laurent R Chiarelli, Giorgia Mori, Beatrice Silvia Orena, Marta Esposito, Thomas Lane, Ana Luisa de Jesus Lopes Ribeiro, Giulia Degiacomi, Júlia Zemanová, Sára Szádocka, Stanislav Huszár, Zuzana Palčeková, Marcello Manfredi, Fabio Gosetti, Joël Lelièvre, Lluis Ballell, Elena Kazakova, Vadim Makarov, Emilio Marengo, Katarina Mikusova, Stewart T Cole, Giovanna Riccardi, Sean Ekins, Maria Rosalia Pasca
Mycobacterium tuberculosis, the etiological agent of the infectious disease tuberculosis, kills approximately 1.5 million people annually, while the spread of multidrug-resistant strains is of great global concern. Thus, continuous efforts to identify new antitubercular drugs as well as novel targets are crucial. Recently, two prodrugs activated by the monooxygenase EthA, 7947882 and 7904688, which target the CTP synthetase PyrG, were identified and characterized. In this work, microbiological, biochemical, and in silico methodologies were used to demonstrate that both prodrugs possess a second target, the pantothenate kinase PanK...
February 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29371252/looking-deep-into-the-eye-of-the-tiger-in-pantothenate-kinase-associated-neurodegeneration
#10
J-H Lee, A Gregory, P Hogarth, C Rogers, S J Hayflick
BACKGROUND AND PURPOSE: A detailed delineation of the MR imaging changes in the globus pallidus in pantothenate kinase-associated neurodegeneration will be helpful for diagnosis and monitoring of patients. The aim of this study was to determine the morphologic spectrum of the "eye-of-the-tiger" sign and the topographic pattern of iron deposition in a group of patients with pantothenate kinase-associated neurodegeneration. MATERIALS AND METHODS: Seventy-four MR imaging scans from 54 individuals with PANK2 mutations were analyzed for signal patterns in the globus pallidus...
January 25, 2018: AJNR. American Journal of Neuroradiology
https://www.readbyqxmd.com/read/29332383/developing-pantetheinase-resistant-pantothenamide-antibacterials-structural-modification-impacts-on-pank-interaction-and-mode-of-action
#11
Leanne Barnard, Konrad J Mostert, Willem A L van Otterlo, Erick Strauss
Pantothenamides (PanAms) are analogues of pantothenate, the biosynthetic precursor of coenzyme A (CoA), and show potent antimicrobial activity against several bacteria and the malaria parasite in vitro. However, pantetheinase enzymes that normally degrade pantetheine in human serum also act on the PanAms, thereby reducing their potency. In this study, we designed analogues of the known antibacterial PanAm N-heptylpantothenamide (N7-Pan) to be resistant to pantetheinase by using three complementary structural modification strategies...
January 23, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29325618/neurodegeneration-with-brain-iron-accumulation
#12
Susan J Hayflick, Manju A Kurian, Penelope Hogarth
Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A2 -associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29233590/structure-activity-analysis-of-cj-15-801-analogues-that-interact-with-plasmodium-falciparum-pantothenate-kinase-and-inhibit-parasite-proliferation
#13
Christina Spry, Alan L Sewell, Yuliya Hering, Mathew V J Villa, Jonas Weber, Stephen J Hobson, Suzannah J Harnor, Sheraz Gul, Rodolfo Marquez, Kevin J Saliba
Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B5 ), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing pantothenate analogues...
January 1, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29135293/-from-the-hallervorden-spatz-eponym-to-the-molecular-terminology
#14
Ferenc Garzuly
INTRODUCTION AND AIM: A combination of Niemann-Pick- and Hallervorden-Spatz diseases led to the death of a 17-year-old boy in 1994. Genetic counseling necessitated further investigations in 2017. Meanwhile, the nomenclature of Hallervorden-Spatz disease has been abandoned. The author analyze the reasons for this change. METHOD: Professional activities of Hallervorden and Spatz during and after the Nazi euthanasia program are presented. Also, the scientific efforts that led to the discovery of the genetic background of the disease and ultimately to its new name are highlighted...
October 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/29107839/efficient-one-pot-enzymatic-synthesis-of-dephospho-coenzyme-a
#15
Krishna Sapkota, Faqing Huang
Dephospho coenzyme A (depCoA) is the last intermediate for CoA biosynthesis, and it can be used as a transcription initiator to prepare CoA-linked RNA by in vitro transcription. However, commercially available depCoA is expensive. We hereby describe a simple and efficient enzymatic synthesis of depCoA in a single-step from commercially available and inexpensive oxidized pantethine (Ox-Pan) and ATP. A plasmid (pCoaDAa) was constructed to co-express and co-purify two enzymes pantothenate kinase (PanK/coaA) and phosphopantetheine adenylyltransferase (PPAT/coaD)...
February 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29095158/biochemical-and-structural-studies-of-mutants-indicate-concerted-movement-of-the-dimer-interface-and-ligand-binding-region-of-mycobacterium-tuberculosis-pantothenate-kinase
#16
A Paul, P Kumar, A Surolia, M Vijayan
Two point mutants and the corresponding double mutant of Mycobacterium tuberculosis pantothenate kinase have been prepared and biochemically and structurally characterized. The mutants were designed to weaken the affinity of the enzyme for the feedback inhibitor CoA. The mutants exhibit reduced activity, which can be explained in terms of their structures. The crystals of the mutants are not isomorphous to any of the previously analysed crystals of the wild-type enzyme or its complexes. The mycobacterial enzyme and its homologous Escherichia coli enzyme exhibit structural differences in their nucleotide complexes in the dimer interface and the ligand-binding region...
November 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/29079738/the-antimalarial-activity-of-the-pantothenamide-%C3%AE-panam-is-via-inhibition-of-pantothenate-phosphorylation
#17
Joy E Chiu, Jose Thekkiniath, Jae-Yeon Choi, Benjamin A Perrin, Lauren Lawres, Mark Plummer, Azan Z Virji, Amanah Abraham, Justin Y Toh, Michael Van Zandt, Ahmed S I Aly, Dennis R Voelker, Choukri Ben Mamoun
The biosynthesis of the major acyl carrier Coenzyme A from pantothenic acid (PA) is critical for survival of Plasmodium falciparum within human erythrocytes. Accordingly, a PA analog α-PanAm showed potent activity against blood stage parasites in vitro; however, its efficacy in vivo and its mode of action remain unknown. We developed a new synthesis route for α-PanAm and showed that the compound is highly effective against blood stages of drug-sensitive and -resistant P. falciparum strains, inhibits development of P...
October 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28941230/effects-of-rumen-protected-pantothenate-supplementation-on-lactation-performance-ruminal-fermentation-nutrient-digestion-and-blood-metabolites-in-dairy-cows
#18
Cong Wang, Qiang Liu, He Qiong Li, Xiao Xu Wu, Gang Guo, Wen Jie Huo, Cai Xia Pei, Yan Li Zhang, Shuan Lin Zhang
BACKGROUND: Lactation performance of dairy cow has considerably increased with animal breeding and management improvement in recent years. Ruminal net synthesised pantothenic acid is insufficient to meet the requirement of high producing dairy cows. The objective was to investigate the effects of rumen-protected pantothenate (RPP) on lactation performance, ruminal fermentation, nutrient digestion and blood metabolites in dairy cows. RESULTS: Dry matter (DM) intake tended to increase, whereas milk yields, milk fat percentage and yield, body condition score (BCS) changes and net energy output except for maintenance increased linearly with increasing RPP supplementation...
April 2018: Journal of the Science of Food and Agriculture
https://www.readbyqxmd.com/read/28900161/acetyl-4-phosphopantetheine-is-stable-in-serum-and-prevents-phenotypes-induced-by-pantothenate-kinase-deficiency
#19
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
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...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28881514/-phenotypic-and-genotypic-features-of-twenty-children-with-classic-pantothenate-kinase-associated-neurodegeneration
#20
J Zhou, J He, L P Kou, H C Feng, Y H Deng, Z B Zhang, L Zhou, J M Wang, Y W Jiang, Y Wu
Objective: To explore the phenotypic and genotypic characteristics in Chinese children with classic pantothenate kinase-associated neurodegeneration (PKAN). Method: The clinical, radiographic and genetic data of all PKAN patients diagnosed at pediatric department of Peking University First Hospital from November 2006 to December 2016 were retrospectively collected and analyzed. Result: Twenty patients with classic PKAN were included in the study. The median age at onset was 3.5 years (ranging from 1.0 to 10...
September 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
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