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pantothenate kinase

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https://www.readbyqxmd.com/read/29453370/a-multitarget-approach-to-drug-discovery-inhibiting-mycobacterium-tuberculosis-pyrg-and-pank
#1
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
#2
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
#3
Leanne Barnard, Konrad Johannes 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 14, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29325618/neurodegeneration-with-brain-iron-accumulation
#4
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
#5
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...
August 25, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29135293/-from-the-hallervorden-spatz-eponym-to-the-molecular-terminology
#6
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
#7
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)...
November 3, 2017: 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
#8
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
#9
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
#10
Wang Cong, Liu Qiang, Li He Qiong, Wu Xiao Xu, Gang Guo, Wen Jie Huo, Pei Cai Xia, Zhang Yan Li, Zhang Shuan Lin
BACKGROUND: Lactation performance of dairy cow has considerably increased with animal breeding and management improvement in recent years. Ruminal net synthesized 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 maintance increased linearly with increasing RPP supplementation...
September 23, 2017: 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
#11
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
#12
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
https://www.readbyqxmd.com/read/28845923/clinical-rating-scale-for-pantothenate-kinase-associated-neurodegeneration-a-pilot-study
#13
Alejandra Darling, Cristina Tello, María Josep Martí, Cristina Garrido, Sergio Aguilera-Albesa, Miguel Tomás Vila, Itziar Gastón, Marcos Madruga, Luis González Gutiérrez, Julio Ramos Lizana, Montserrat Pujol, Tania Gavilán Iglesias, Kylee Tustin, Jean Pierre Lin, Giovanna Zorzi, Nardo Nardocci, Loreto Martorell, Gustavo Lorenzo Sanz, Fuencisla Gutiérrez, Pedro J García, Lidia Vela, Carlos Hernández Lahoz, Juan Darío Ortigoza Escobar, Laura Martí Sánchez, Fradique Moreira, Miguel Coelho, Leonor Correia Guedes, Ana Castro Caldas, Joaquim Ferreira, Paula Pires, Cristina Costa, Paulo Rego, Marina Magalhães, María Stamelou, Daniel Cuadras Pallejà, Carmen Rodríguez-Blazquez, Pablo Martínez-Martín, Vincenzo Lupo, Leonidas Stefanis, Roser Pons, Carmen Espinós, Teresa Temudo, Belén Pérez Dueñas
BACKGROUND: Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration. METHODS: In this international cross-sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment...
August 28, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28781879/novel-pank2-mutation-in-the-first-greek-compound-heterozygote-patient-with-pantothenate-kinase-associated-neurodegeneration
#14
George P Paraskevas, Christos Yapijakis, Anastasia Bougea, Vasilios Constantinides, Mara Bourbouli, Eleftherios Stamboulis, Elisabeth Kapaki
Pantothenate-kinase-associated neurodegeneration is the most common autosomal recessive form of neurodegeneration with brain iron accumulation. Less than 100 mutations in PANK2 gene (20p13) are responsible for classic and atypical cases. We report here the first Greek case of atypical pantothenate-kinase-associated neurodegeneration, confirmed by molecular analysis that revealed two trans-acting mutations. Our findings highlight the possible role of rare variants contributing to disease risk and possibly to variable clinical phenotype...
2017: SAGE Open Medical Case Reports
https://www.readbyqxmd.com/read/28681788/atypical-pantothenate-kinase-associated-neurodegeneration-with-novel-genetic-mutation
#15
Anil V Israni, Anirban Mandal
No abstract text is available yet for this article.
July 2017: Neurology India
https://www.readbyqxmd.com/read/28680084/a-variation-in-pank2-gene-is-causing-pantothenate-kinase-associated-neurodegeneration-in-a-family-from-jammu-and-kashmir-india
#16
Arshia Angural, Inderpal Singh, Ankit Mahajan, Pranav Pandoh, Manoj K Dhar, Sanjana Kaul, Vijeshwar Verma, Ekta Rai, Sushil Razdan, Kamal Kishore Pandita, Swarkar Sharma
Pantothenate kinase-associated neurodegeneration is a rare hereditary neurodegenerative disorder associated with nucleotide variation(s) in mitochondrial human Pantothenate kinase 2 (hPanK2) protein encoding PANK2 gene, and is characterized by symptoms of extra-pyramidal dysfunction and accumulation of non-heme iron predominantly in the basal ganglia of the brain. In this study, we describe a familial case of PKAN from the State of Jammu and Kashmir (J&K), India based on the clinical findings and genetic screening of two affected siblings born to consanguineous normal parents...
July 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28676844/genetic-characterization-of-coenzyme-a-biosynthesis-reveals-essential-distinctive-functions-during-malaria-parasite-development-in-blood-and-mosquito
#17
Robert J Hart, Amanah Abraham, Ahmed S I Aly
Coenzyme A (CoA) is an essential universal cofactor for all prokaryotic and eukaryotic cells. In nearly all non-photosynthetic cells, CoA biosynthesis depends on the uptake and phosphorylation of vitamin B5 (pantothenic acid or pantothenate). Recently, putative pantothenate transporter (PAT) and pantothenate kinases (PanKs) were functionally characterized in P. yoelii. PAT and PanKs were shown to be dispensable for blood stage development, but they were essential for mosquito stages development. Yet, little is known about the cellular functions of the other enzymes of the CoA biosynthesis pathway in malaria parasite life cycle stages...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28629633/atypical-pantothenate-kinase-associated-neurodegeneration-clinical-description-of-two-brothers-and-a-review-of-the-literature
#18
S Mahoui, A Benhaddadi, W Ameur El Khedoud, M Abada Bendib, M Chaouch
Two clinical forms of pantothenate kinase-associated neurodegeneration (PKAN) have been described: typical PKAN and atypical PKAN. Atypical PKAN has later onset and a slower course of disease. This report describes two siblings with the atypical form of PKAN, combining dystonia, irritability and a dysmorphia syndrome. In addition, a review of the literature was carried out for all published cases of atypical PKAN to gather descriptions of its various clinical presentations, age of onset and MRI findings, and to highlight the different treatments used for PKAN patients...
June 16, 2017: Revue Neurologique
https://www.readbyqxmd.com/read/28567317/open-label-fosmetpantotenate-a-phosphopantothenate-replacement-therapy-in-a-single-patient-with-atypical-pkan
#19
Yiolanda-Panayiota Christou, George A Tanteles, Elena Kkolou, Annita Ormiston, Kostas Konstantopoulos, Maria Beconi, Randall D Marshall, Horacio Plotkin, Kleopas A Kleopa
Objective. Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder with variable onset, rate of progression, and phenotypic expression. Later-onset, more slowly progressive PKAN often presents with neuropsychiatric as well as motor manifestations that include speech difficulties, progressive dystonia, rigidity, and parkinsonism. PKAN is caused by biallelic PANK2 mutations, a gene that encodes pantothenate kinase 2, a regulatory enzyme in coenzyme A biosynthesis. Current therapeutic strategies rely on symptomatic relief...
2017: Case Reports in Neurological Medicine
https://www.readbyqxmd.com/read/28489334/diagnosis-of-copan-by-whole-exome-sequencing-waking-up-a-sleeping-tiger-s-eye
#20
Christina Evers, Angelika Seitz, Birgit Assmann, Thomas Opladen, Stephanie Karch, Katrin Hinderhofer, Martin Granzow, Nagarajan Paramasivam, Roland Eils, Nicolle Diessl, Claus R Bartram, Ute Moog
Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative disorders characterized by iron accumulation in the basal ganglia. Recently, mutations in CoA synthase (COASY) have been identified as a cause of a novel NBIA subtype (COASY Protein-Associated Neurodegeneration, CoPAN) in two patients with dystonic paraparesis, parkinsonian features, cognitive impairment, behavior abnormalities, and axonal neuropathy. COASY encodes an enzyme required for Coenzyme A (CoA) biosynthesis. Using whole exome sequencing (WES) we identified compound heterozygous COASY mutations in two siblings with intellectual disability, ataxic gait, progressive spasticity, and obsessive-compulsive behavior...
May 10, 2017: American Journal of Medical Genetics. Part A
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