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pantothenate kinase

Scott J Hughes, Leanne Barnard, Katayoun Mottaghi, Wolfram Tempel, Tetyana Antoshchenko, Bum Soo Hong, Abdellah Allali-Hassani, David Smil, Masoud Vedadi, Erick Strauss, Hee-Won Park
The potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) has been shown to at least partially be due to the inhibition of Staphylococcus aureus's atypical type II pantothenate kinase (SaPanKII), the first enzyme of coenzyme A biosynthesis. This mechanism of action follows from SaPanKII having a binding mode for PanAms that is distinct from those of other PanKs. To dissect the molecular interactions responsible for PanAm inhibitory activity, we conducted a mini SAR study in tandem with the cocrystallization of SaPanKII with two classic PanAms (N5-Pan and N7-Pan), culminating in the synthesis and characterization of two new PanAms, N-Pip-PanAm and MeO-N5-PanAm...
September 9, 2016: ACS Infectious Diseases
Vanessa M Howieson, Elisa Tran, Annabelle Hoegl, Han Ling Fam, Jonathan Fu, Kate Sivonen, Xiao Xuan Li, Karine Auclair, Kevin J Saliba
The biosynthesis of CoA from pantothenate and the utilization of CoA in essential biochemical pathways represent promising antimalarial drug targets. Pantothenamides, amide-bearing pantothenate analogues, have potential as antimalarials, but a serum enzyme called pantetheinase degrades pantothenamides, rendering them inactive in vivo In this study we characterize a series of 19 compounds that mimic pantothenamides with a stable triazole group instead of the labile amide. Two of these pantothenamides are active against the intraerythrocytic stage parasite with IC50 values of ∼50 nM and three others have sub-micromolar IC50 values...
September 19, 2016: Antimicrobial Agents and Chemotherapy
Robert J Hart, Emmanuel Cornillot, Amanah Abraham, Emily Molina, Catherine S Nation, Choukri Ben Mamoun, Ahmed S I Aly
The metabolic machinery for the biosynthesis of Coenzyme A (CoA) from exogenous pantothenic acid (Vitamin B5) has long been considered as an excellent target for the development of selective antimicrobials. Earlier studies in the human malaria parasite Plasmodium falciparum have shown that pantothenate analogs interfere with pantothenate phosphorylation and block asexual blood stage development. Although two eukaryotic-type putative pantothenate kinase genes (PanK1 and PanK2) have been identified in all malaria parasite species, their role in the development of Plasmodium life cycle stages remains unknown...
2016: Scientific Reports
Chitra Subramanian, Mi-Kyung Yun, Jiangwei Yao, Lalit Kumar Sharma, Richard E Lee, Stephen W White, Suzanne Jackowski, Charles O Rock
Pantothenate kinase is the master regulator of CoA biosynthesis and is feedback-inhibited by acetyl-CoA. Comparison of the human PANK3·acetyl-CoA complex to the structures of PANK3 in four catalytically relevant complexes, 5'-adenylyl-β,γ-imidodiphosphate (AMPPNP)·Mg(2+), AMPPNP·Mg(2+)·pantothenate, ADP·Mg(2+)·phosphopantothenate, and AMP phosphoramidate (AMPPN)·Mg(2+), revealed a large conformational change in the dimeric enzyme. The amino-terminal nucleotide binding domain rotates to close the active site, and this allows the P-loop to engage ATP and facilitates required substrate/product interactions at the active site...
October 14, 2016: Journal of Biological Chemistry
Daniel I Orellana, Paolo Santambrogio, Alicia Rubio, Latefa Yekhlef, Cinzia Cancellieri, Sabrina Dusi, Serena G Giannelli, Paola Venco, Pietro G Mazzara, Anna Cozzi, Maurizio Ferrari, Barbara Garavaglia, Stefano Taverna, Valeria Tiranti, Vania Broccoli, Sonia Levi
Pantothenate kinase-associated neurodegeneration (PKAN) is an early onset and severely disabling neurodegenerative disease for which no therapy is available. PKAN is caused by mutations in PANK2, which encodes for the mitochondrial enzyme pantothenate kinase 2. Its function is to catalyze the first limiting step of Coenzyme A (CoA) biosynthesis. We generated induced pluripotent stem cells from PKAN patients and showed that their derived neurons exhibited premature death, increased ROS production, mitochondrial dysfunctions-including impairment of mitochondrial iron-dependent biosynthesis-and major membrane excitability defects...
October 4, 2016: EMBO Molecular Medicine
Yan-Fang Li, Hong-Fu Li, Yan-Bin Zhang, Ji-Min Wu
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive neurodegenerative disorder resulting from pantothenate kinase 2 (PANK2) gene mutations. It is clinically characterized by early onset of extrapyramidal symptoms, with or without pigmentary retinopathy, optic atrophy and acanthocytosis. The specific radiographic appearance of PKAN is the eye-of-the-tiger sign. However, there are few studies regarding PKAN patients of Chinese Han ancestry. In the present study, a Chinese 20-year-old female with an 8-year history of unsteady walking and involuntary movements is described...
August 2016: Biomedical Reports
Lili Huang, Anna Khusnutdinova, Boguslaw Nocek, Greg Brown, Xiaohui Xu, Hong Cui, Pierre Petit, Robert Flick, Rémi Zallot, Kelly Balmant, Michael J Ziemak, John Shanklin, Valérie de Crécy-Lagard, Oliver Fiehn, Jesse F Gregory, Andrzej Joachimiak, Alexei Savchenko, Alexander F Yakunin, Andrew D Hanson
DUF89 family proteins occur widely in both prokaryotes and eukaryotes, but their functions are unknown. Here we define three DUF89 subfamilies (I, II, and III), with subfamily II being split into stand-alone proteins and proteins fused to pantothenate kinase (PanK). We demonstrated that DUF89 proteins have metal-dependent phosphatase activity against reactive phosphoesters or their damaged forms, notably sugar phosphates (subfamilies II and III), phosphopantetheine and its S-sulfonate or sulfonate (subfamily II-PanK fusions), and nucleotides (subfamily I)...
August 2016: Nature Chemical Biology
Muhammad Yousaf, Raghu H Ramakrishnaiah, Chhavi Kaushik, Manoj Kumar, Chetan Chandulal Shah
Pantothenate kinase 2 deficiency (previously known as Hallervorden-Spatz disease) is an unusual metabolic disorder characterized by progressive extrapyramidal dysfunction and dementia. A 27-year-old Caucasian presented with a major depression disorder and social phobia since adolescence. Patient had marked paranoia, auditory hallucinations, extrapyramidal dysfunction, poor memory, and gait abnormality. Laboratory tests including serum copper and ceruloplasmin were all normal. Magnetic resonance imaging (MRI) examination of the brain played an important role in the diagnosis in this patient...
2009: Radiology case reports
Sunil Gothwal, Swati Nayan
Hallervorden-Spatz syndrome is a disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. The disease is caused by mutations in gene encoding pantothenate kinase 2 (PANK2) and patients have pantothenate kinase-associated neurodegeneration. We present an 8-year-old boy with progressive muscle dystonia, neuroregression, frequent fall and multiple injury marks of different stages. Seizures are rare with PANK2. This child had seizure onset at 4 years of age and seizure free on valproate and levetricetam...
April 2016: Basic and Clinical Neuroscience
Zuhal Yapici, Nihan Hande Akcakaya, Pinar Tekturk, Sibel Aylin Ugur Iseri, Ugur Ozbek
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurodegenerative condition. Major clinical features include progressive dystonia, pigmentary retinopathy, spasticity, and cognitive decline. The typical MRI sign of the disease, known as "eye-of-the-tiger", is what makes differential diagnosis possible. We here describe a 16-year-old male patient with PKAN presenting with severe and sustained jaw-opening dystonia which may be due to heterogeneous etiologies showing poor response to treatment...
September 2016: Brain & Development
Takahiro Shimosaka, Hiroya Tomita, Haruyuki Atomi
UNLABELLED: Regulation of coenzyme A (CoA) biosynthesis in bacteria and eukaryotes occurs through feedback inhibition targeting type I and type II pantothenate kinase (PanK), respectively. In contrast, the activity of type III PanK is not affected by CoA. As the hyperthermophilic bacterium Thermotoga maritima harbors only a single type III PanK (Tm-PanK), here we examined the mechanisms that regulate CoA biosynthesis in this organism. We first examined the enzyme responsible for the ketopantoate reductase (KPR) reaction, which is the target of feedback inhibition in archaea...
July 15, 2016: Journal of Bacteriology
Chris J Radoux, Tjelvar S G Olsson, Will R Pitt, Colin R Groom, Tom L Blundell
Locating a ligand-binding site is an important first step in structure-guided drug discovery, but current methods do little to suggest which interactions within a pocket are the most important for binding. Here we illustrate a method that samples atomic hotspots with simple molecular probes to produce fragment hotspot maps. These maps specifically highlight fragment-binding sites and their corresponding pharmacophores. For ligand-bound structures, they provide an intuitive visual guide within the binding site, directing medicinal chemists where to grow the molecule and alerting them to suboptimal interactions within the original hit...
May 12, 2016: Journal of Medicinal Chemistry
Petr Dusek, Susanne A Schneider, Jan Aaseth
Disturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration...
December 2016: Journal of Trace Elements in Medicine and Biology
Jochen Hinkelbein, Armin Kalenka, Markus Alb
BACKGROUND: Hallervorden-Spatz disease (HSD) is a rare, progressive neurodegenerative disorder; the new and preferred name for HSD is 'pantothenate-kinase-associated neurodegeneration' (PKAN). Other suggested names are 'neurodegeneration with brain iron accumulation type 1' or 'infantile neuroaxonal dystrophy'. Patients with PKAN have many complications, which lead to numerous anesthetic management challenges. Reports concerning the anesthetic management of patients with PKAN are very limited...
June 2006: Acta Neuropsychiatrica
Magne Nylenna, Noralv Breivik, Arvid Heiberg, Øivind Larsen
Was district medical officer Jensen the first doctor to describe patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) in Volda in 1830? A case series of four siblings with the same disease written by district medical officer Peter Jensen (1799-1832) in Aalesund in 1830, was published in the Norwegian medical journal Eyr in 1832. The children, who were healthy almost up to school age, developed dystonic involuntary movements and deformities in all extremities, lost their ability to speak and were emaciated before they died at around the age of nine years...
March 15, 2016: Tidsskrift for Den Norske Lægeforening: Tidsskrift for Praktisk Medicin, Ny Række
Marios Panas, Konstantinos Spengos, Georgios Koutsis, Georgios Tsivgoulis, Konstantinos Sfagos, Nikolaos Kalfakis, Dimitris Vassilopoulos
BACKGROUND: Hallervorden-Spatz syndrome is characterized by pyramidal and extrapyramidal signs, and dysarthria and dementia. Psychiatric symptomatology can emerge in the course of the disorder. Mutations in the pantothenate kinase 2 gene have been found in many cases. We report a case with psychosis as sole presenting symptom. CASE: A 41-year-old man presented with change in behavior and paranoid delusional ideation. Six months later, spasticity, extrapyramidal rigidity and dysarthria were added to the picture...
April 2007: Acta Neuropsychiatrica
Virginia Schadeweg, Eckhard Boles
BACKGROUND: Butanol isomers are regarded as more suitable fuel substitutes than bioethanol. n-Butanol is naturally produced by some Clostridia species, but due to inherent problems with clostridial fermentations, industrially more relevant organisms have been genetically engineered for n-butanol production. Although the yeast Saccharomyces cerevisiae holds significant advantages in terms of scalable industrial fermentation, n-butanol yields and titers obtained so far are only low. RESULTS: Here we report a thorough analysis and significant improvements of n-butanol production from glucose with yeast via the acetoacetyl-CoA-derived pathway...
2016: Biotechnology for Biofuels
Jinu Han, Do Wook Kim, Chul-Ho Lee, Sueng-Han Han
Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegeneration with brain iron accumulation and characterized by extrapyramidal signs, vision loss, and intellectual decline. PKAN is caused by mutations in the PANK2 gene, which codes for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the coenzyme A biosynthetic pathway. Visual failure in this disorder is typically due to pigmentary retinopathy. Yet our patient, a 13-year-old girl with PKAN, developed bilateral optic atrophy and the appearance of the retina and electroretinography were normal...
June 2016: Journal of Neuro-ophthalmology: the Official Journal of the North American Neuro-Ophthalmology Society
Jae-Hyeok Lee, Jongkyu Park, Ho-Sung Ryu, Hyeyoung Park, Young Eun Kim, Jin Yong Hong, Sang Ook Nam, Young-Hee Sung, Seung-Hwan Lee, Jee-Young Lee, Myung Jun Lee, Tae-Hyoung Kim, Chul Hyoung Lyoo, Sun Ju Chung, Seong Beom Koh, Phil Hyu Lee, Jin Whan Cho, Mee Young Park, Yun Joong Kim, Young H Sohn, Beom Seok Jeon, Myung Sik Lee
OBJECTIVE: Neurodegeneration with brain iron accumulation (NBIA) represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea. METHODS: We collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature...
January 2016: Journal of Movement Disorders
Jamil A Shilpi, Mohammad Tuhin Ali, Sanjib Saha, Shihab Hasan, Alexander I Gray, Véronique Seidel
PURPOSE: There is an urgent need to discover and develop new drugs to combat Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) in humans. In recent years, there has been a renewed interest in the discovery of new anti-TB agents from natural sources. In the present investigation, molecular docking studies were carried out on two ellagic acid derivatives, namely pteleoellagic acid (1) isolated from Ludwigia adscendens, and 3,3'-di-O-methyl ellagic acid 4-O-α-rhamnopyranoside (2) isolated from Trewia nudiflora, to investigate their binding to two enzymes involved in M...
December 2015: In Silico Pharmacology
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