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[PMID]:29178642
[Au] Autor:Thompson JA; De Roach JN; McLaren TL; Montgomery HE; Hoffmann LH; Campbell IR; Chen FK; Mackey DA; Lamey TM
[Ad] Endereço:Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
[Ti] Título:The genetic profile of Leber congenital amaurosis in an Australian cohort.
[So] Source:Mol Genet Genomic Med;5(6):652-667, 2017 11.
[Is] ISSN:2324-9269
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Leber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. LCA encompasses a group of heterogeneous disorders, with 24 genes currently implicated in pathogenesis. Such clinical and genetic heterogeneity poses great challenges for treatment, with personalized therapies anticipated to be the best treatment candidates. Unraveling the individual genetic etiology of disease is a prerequisite for personalized therapies, and could identify potential treatment candidates, inform patient management, and discriminate syndromic forms of disease. METHODS: We have genetically analyzed 45 affected and 82 unaffected individuals from 34 unrelated LCA pedigrees using predominantly next-generation sequencing and Array CGH technology. RESULTS: We present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank. CEP290 and GUCY2D mutations, each represent 19% of unrelated LCA cases, followed by NMNAT1 (12%). Genetic subtypes were consistent with other reports, and were resolved in 90% of this cohort. CONCLUSION: The high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non-hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first-tier test for LCA.
[Mh] Termos MeSH primário: Amaurose Congênita de Leber/genética
Grupo com Ancestrais Oceânicos/genética
[Mh] Termos MeSH secundário: Antígenos de Neoplasias/genética
Austrália/epidemiologia
Estudos de Coortes
Análise Mutacional de DNA
Bases de Dados Genéticas
Proteínas do Olho/genética
Guanilato Ciclase/genética
Heterozigoto
Sequenciamento de Nucleotídeos em Larga Escala
Homozigoto
Seres Humanos
Amaurose Congênita de Leber/diagnóstico
Amaurose Congênita de Leber/epidemiologia
Proteínas Associadas aos Microtúbulos/genética
Proteínas de Neoplasias/genética
Nicotinamida-Nucleotídeo Adenililtransferase/genética
Linhagem
Fenótipo
Prevalência
Receptores de Superfície Celular/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Cep290 protein, human); 0 (Eye Proteins); 0 (Microtubule-Associated Proteins); 0 (Neoplasm Proteins); 0 (Receptors, Cell Surface); 0 (guanylate cyclase 1); 0 (lebercilin protein, human); EC 2.7.7.1 (NMNAT1 protein, human); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase); EC 4.6.1.2 (Guanylate Cyclase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1002/mgg3.321


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[PMID]:28455340
[Au] Autor:Wang X; Zhou YJ; Wang L; Liu W; Liu Y; Peng C; Zhao ZK
[Ad] Endereço:Division of Biotechnology, Dalian Institute of Chemical Physics, CAS, Dalian, People's Republic of China.
[Ti] Título:Engineering Escherichia coli Nicotinic Acid Mononucleotide Adenylyltransferase for Fully Active Amidated NAD Biosynthesis.
[So] Source:Appl Environ Microbiol;83(13), 2017 Jul 01.
[Is] ISSN:1098-5336
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:NAD and its reduced form NADH function as essential redox cofactors and have major roles in determining cellular metabolic features. NAD can be synthesized through the deamidated and amidated pathways, for which the key reaction involves adenylylation of nicotinic acid mononucleotide (NaMN) and nicotinamide mononucleotide (NMN), respectively. In , NAD biosynthesis depends on the protein NadD-catalyzed adenylylation of NaMN to nicotinic acid adenine dinucleotide (NaAD), followed by NAD synthase-catalyzed amidation. In this study, we engineered NadD to favor NMN for improved amidated pathway activity. We designed NadD mutant libraries, screened by a malic enzyme-coupled colorimetric assay, and identified two variants, 11B4 (Y84V/Y118D) and 16D8 (A86W/Y118N), with a high preference for NMN. Whereas in the presence of NMN both variants were capable of enabling the viability of cells of BW25113-derived NAD-auxotrophic strain YJE003, for which the last step of the deamidated pathway is blocked, the 16D8 expression strain could grow without exogenous NMN and accumulated a higher cellular NAD(H) level than BW25113 in the stationary phase. These mutants established fully active amidated NAD biosynthesis and offered a new opportunity to manipulate NAD metabolism for biocatalysis and metabolic engineering. Adenylylation of nicotinic acid mononucleotide (NaMN) and adenylylation of nicotinamide mononucleotide (NMN), respectively, are the key steps in the deamidated and amidated pathways for NAD biosynthesis. In most organisms, canonical NAD biosynthesis follows the deamidated pathway. Here we engineered NaMN adenylyltransferase to favor NMN and expressed the mutant enzyme in an NAD-auxotrophic strain that has the last step of the deamidated pathway blocked. The engineered strain survived in M9 medium, which indicated the implementation of a functional amidated pathway for NAD biosynthesis. These results enrich our understanding of NAD biosynthesis and are valuable for manipulation of NAD homeostasis for metabolic engineering.
[Mh] Termos MeSH primário: Escherichia coli/enzimologia
NAD/biossíntese
Nicotinamida-Nucleotídeo Adenililtransferase/genética
[Mh] Termos MeSH secundário: Escherichia coli/química
Escherichia coli/genética
Escherichia coli/metabolismo
Mutação
NAD/análogos & derivados
NAD/metabolismo
Mononucleotídeo de Nicotinamida/análogos & derivados
Mononucleotídeo de Nicotinamida/metabolismo
Nicotinamida-Nucleotídeo Adenililtransferase/química
Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo
Engenharia de Proteínas
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0U46U6E8UK (NAD); 1094-61-7 (Nicotinamide Mononucleotide); 321-02-8 (nicotinate mononucleotide); 6450-77-7 (nicotinic acid adenine dinucleotide); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase); EC 2.7.7.18 (nicotinic acid mononucleotide adenylyltransferase)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171225
[Lr] Data última revisão:
171225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:28683272
[Au] Autor:Neukomm LJ; Burdett TC; Seeds AM; Hampel S; Coutinho-Budd JC; Farley JE; Wong J; Karadeniz YB; Osterloh JM; Sheehan AE; Freeman MR
[Ad] Endereço:Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: lukas.neukomm@gmail.com.
[Ti] Título:Axon Death Pathways Converge on Axundead to Promote Functional and Structural Axon Disassembly.
[So] Source:Neuron;95(1):78-91.e5, 2017 Jul 05.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Axon degeneration is a hallmark of neurodegenerative disease and neural injury. Axotomy activates an intrinsic pro-degenerative axon death signaling cascade involving loss of the NAD biosynthetic enzyme Nmnat/Nmnat2 in axons, activation of dSarm/Sarm1, and subsequent Sarm-dependent depletion of NAD . Here we identify Axundead (Axed) as a mediator of axon death. axed mutants suppress axon death in several types of axons for the lifespan of the fly and block the pro-degenerative effects of activated dSarm in vivo. Neurodegeneration induced by loss of the sole fly Nmnat ortholog is also fully blocked by axed, but not dsarm, mutants. Thus, pro-degenerative pathways activated by dSarm signaling or Nmnat elimination ultimately converge on Axed. Remarkably, severed axons morphologically preserved by axon death pathway mutations remain integrated in circuits and able to elicit complex behaviors after stimulation, indicating that blockade of axon death signaling results in long-term functional preservation of axons.
[Mh] Termos MeSH primário: Proteínas do Domínio Armadillo/genética
Axônios/metabolismo
Proteínas do Citoesqueleto/genética
Proteínas de Drosophila/genética
Nicotinamida-Nucleotídeo Adenililtransferase/genética
Degeneração Walleriana/genética
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Proteínas do Domínio Armadillo/metabolismo
Antenas de Artrópodes/lesões
Antenas de Artrópodes/inervação
Axotomia
Comportamento Animal
Western Blotting
Linhagem Celular
Proteínas do Citoesqueleto/metabolismo
Proteínas de Drosophila/metabolismo
Drosophila melanogaster
Asseio Animal
Imunidade Ativa
NAD/metabolismo
Neurônios/metabolismo
Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo
Optogenética
Degeneração Walleriana/metabolismo
Asas de Animais/lesões
Asas de Animais/inervação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Armadillo Domain Proteins); 0 (Cytoskeletal Proteins); 0 (Drosophila Proteins); 0 (Sarm protein, Drosophila); 0 (axundead protein, Drosophila); 0U46U6E8UK (NAD); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE


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[PMID]:28648779
[Au] Autor:Sedlyarova N; Rescheneder P; Magán A; Popitsch N; Rziha N; Bilusic I; Epshtein V; Zimmermann B; Lybecker M; Sedlyarov V; Schroeder R; Nudler E
[Ad] Endereço:Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Dr. Bohrgasse 9/5, 1030 Vienna, Austria.
[Ti] Título:Natural RNA Polymerase Aptamers Regulate Transcription in E. coli.
[So] Source:Mol Cell;67(1):30-43.e6, 2017 Jul 06.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In search for RNA signals that modulate transcription via direct interaction with RNA polymerase (RNAP), we deep sequenced an E. coli genomic library enriched for RNAP-binding RNAs. Many natural RNAP-binding aptamers, termed RAPs, were mapped to the genome. Over 60% of E. coli genes carry RAPs in their mRNA. Combining in vitro and in vivo approaches, we characterized a subset of inhibitory RAPs (iRAPs) that promote Rho-dependent transcription termination. A representative iRAP within the coding region of the essential gene, nadD, greatly reduces its transcriptional output in stationary phase and under oxidative stress, demonstrating that iRAPs control gene expression in response to changing environment. The mechanism of iRAPs involves active uncoupling of transcription and translation, making nascent RNA accessible to Rho. iRAPs encoded in the antisense strand also promote gene expression by reducing transcriptional interference. In essence, our work uncovers a broad class of cis-acting RNA signals that globally control bacterial transcription.
[Mh] Termos MeSH primário: Aptâmeros de Nucleotídeos/genética
Proteínas de Bactérias/genética
RNA Polimerases Dirigidas por DNA/genética
Escherichia coli/genética
Técnica de Seleção de Aptâmeros
Terminação da Transcrição Genética
[Mh] Termos MeSH secundário: Aptâmeros de Nucleotídeos/metabolismo
Proteínas de Bactérias/metabolismo
RNA Polimerases Dirigidas por DNA/metabolismo
Escherichia coli/enzimologia
Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Regulação Bacteriana da Expressão Gênica
Genoma Bacteriano
Nicotinamida-Nucleotídeo Adenililtransferase/genética
Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo
Fases de Leitura Aberta
Ribossomos/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aptamers, Nucleotide); 0 (Bacterial Proteins); 0 (Escherichia coli Proteins); 0 (Rho protein, E coli); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase); EC 2.7.7.18 (nicotinic acid mononucleotide adenylyltransferase); EC 2.7.7.6 (DNA-Directed RNA Polymerases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE


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[PMID]:28618168
[Au] Autor:Booth WT; Morris TL; Mysona DP; Shah MJ; Taylor LK; Karlin TW; Clary K; Majorek KA; Offermann LR; Chruszcz M
[Ad] Endereço:Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA.
[Ti] Título:Streptococcus pyogenes quinolinate-salvage pathway-structural and functional studies of quinolinate phosphoribosyl transferase and NH -dependent NAD synthetase.
[So] Source:FEBS J;284(15):2425-2441, 2017 Aug.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Streptococcus pyogenes, also known as Group A Strep (GAS), is an obligate human pathogen that is responsible for millions of infections and numerous deaths per year. Infection manifestations can range from simple, acute pharyngitis to more complex, necrotizing fasciitis. To date, most treatments for GAS infections involve the use of common antibiotics including tetracycline and clindamycin. Unfortunately, new strains have been identified that are resistant to these drugs, therefore, new targets must be identified to treat drug-resistant strains. This work is focused on the structural and functional characterization of three proteins: spNadC, spNadD, and spNadE. These enzymes are involved in the biosynthesis of nicotinamide adenine dinucleotide (NAD ). The structures of spNadC and spNadE were determined. SpNadC is suggested to play a role in GAS virulence, while spNadE, functions as an NAD synthetase and is considered to be a new drug target. Determination of the spNadE structure uncovered a putative, NH channel, which may provide insight into the mechanistic details of NH -dependent NAD synthetases in prokaryotes. ENZYMES: Quinolinate phosphoribosyltransferase: EC2.4.2.19 and NAD synthetase: EC6.3.1.5. DATABASE: Protein structures for spNadC, spNadC , and spNadE are deposited into Protein Data Bank under the accession codes 5HUL, 5HUO & 5HUP, and 5HUH & 5HUJ, respectively.
[Mh] Termos MeSH primário: Amida Sintases/metabolismo
Proteínas de Bactérias/metabolismo
Modelos Moleculares
Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo
Pentosiltransferases/metabolismo
Ácido Quinolínico/metabolismo
Streptococcus pyogenes/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/química
Trifosfato de Adenosina/metabolismo
Amida Sintases/química
Amida Sintases/genética
Apoenzimas/química
Apoenzimas/genética
Apoenzimas/metabolismo
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Sítios de Ligação
Domínio Catalítico
Análise por Conglomerados
Biologia Computacional
Cristalografia por Raios X
Dimerização
Deleção de Genes
Nicotinamida-Nucleotídeo Adenililtransferase/química
Nicotinamida-Nucleotídeo Adenililtransferase/genética
Pentosiltransferases/química
Pentosiltransferases/genética
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Estrutura Quaternária de Proteína
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Homologia Estrutural de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoenzymes); 0 (Bacterial Proteins); 0 (Recombinant Proteins); 8L70Q75FXE (Adenosine Triphosphate); EC 2.4.2.- (Pentosyltransferases); EC 2.4.2.19 (nicotinate-nucleotide diphosphorylase (carboxylating)); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase); EC 2.7.7.18 (nicotinic acid mononucleotide adenylyltransferase); EC 6.3.1.- (Amide Synthases); EC 6.3.1.5 (NAD+ synthase); F6F0HK1URN (Quinolinic Acid)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14136


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[PMID]:28209901
[Au] Autor:Williams PA; Harder JM; Foxworth NE; Cochran KE; Philip VM; Porciatti V; Smithies O; John SW
[Ad] Endereço:The Jackson Laboratory, Bar Harbor, ME 04609, USA.
[Ti] Título:Vitamin B modulates mitochondrial vulnerability and prevents glaucoma in aged mice.
[So] Source:Science;355(6326):756-760, 2017 02 17.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glaucomas are neurodegenerative diseases that cause vision loss, especially in the elderly. The mechanisms initiating glaucoma and driving neuronal vulnerability during normal aging are unknown. Studying glaucoma-prone mice, we show that mitochondrial abnormalities are an early driver of neuronal dysfunction, occurring before detectable degeneration. Retinal levels of nicotinamide adenine dinucleotide (NAD , a key molecule in energy and redox metabolism) decrease with age and render aging neurons vulnerable to disease-related insults. Oral administration of the NAD precursor nicotinamide (vitamin B ), and/or gene therapy (driving expression of , a key NAD -producing enzyme), was protective both prophylactically and as an intervention. At the highest dose tested, 93% of eyes did not develop glaucoma. This supports therapeutic use of vitamin B in glaucoma and potentially other age-related neurodegenerations.
[Mh] Termos MeSH primário: Envelhecimento/metabolismo
Glaucoma/prevenção & controle
Mitocôndrias/efeitos dos fármacos
NAD/deficiência
Doenças Neurodegenerativas/prevenção & controle
Niacinamida/administração & dosagem
[Mh] Termos MeSH secundário: Envelhecimento/patologia
Animais
Senescência Celular
Terapia Genética
Glaucoma/patologia
Camundongos
Mitocôndrias/patologia
Doenças Neurodegenerativas/patologia
Neurônios/metabolismo
Neurônios/patologia
Niacinamida/metabolismo
Niacinamida/farmacologia
Nicotinamida-Nucleotídeo Adenililtransferase/genética
Células Ganglionares da Retina/efeitos dos fármacos
Células Ganglionares da Retina/metabolismo
Células Ganglionares da Retina/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0U46U6E8UK (NAD); 25X51I8RD4 (Niacinamide); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase); EC 2.7.7.1 (Nmnat1 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170218
[St] Status:MEDLINE
[do] DOI:10.1126/science.aal0092


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[PMID]:28202539
[Au] Autor:Gupte R; Liu Z; Kraus WL
[Ad] Endereço:Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
[Ti] Título:PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes.
[So] Source:Genes Dev;31(2):101-126, 2017 Jan 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.
[Mh] Termos MeSH primário: Poli(ADP-Ribose) Polimerases/metabolismo
[Mh] Termos MeSH secundário: Animais
Reparo do DNA/genética
Ativação Enzimática
Interações Hospedeiro-Patógeno
Seres Humanos
Biologia Molecular/tendências
Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo
Transdução de Sinais/genética
Transcrição Genética/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170715
[Lr] Data última revisão:
170715
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170217
[St] Status:MEDLINE
[do] DOI:10.1101/gad.291518.116


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[PMID]:28167526
[Au] Autor:Lee JY; Li Z; Miller ES
[Ad] Endereço:Department of Plant & Microbial Biology, North Carolina State University, Raleigh, North Carolina, USA.
[Ti] Título:Vibrio Phage KVP40 Encodes a Functional NAD Salvage Pathway.
[So] Source:J Bacteriol;199(9), 2017 May 01.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The genome of T4-type bacteriophage KVP40 has five genes predicted to encode proteins of pyridine nucleotide metabolism, of which two, and , would suffice for an NAD salvage pathway. NadV is an apparent nicotinamide phosphoribosyltransferase (NAmPRTase), and NatV is an apparent bifunctional nicotinamide mononucleotide adenylyltransferase (NMNATase) and nicotinamide-adenine dinucleotide pyrophosphatase (Nudix hydrolase). Genes encoding the predicted salvage pathway were cloned and expressed in , the proteins were purified, and their enzymatic properties were examined. KVP40 NadV NAmPRTase is active , and a clone complements a mutant defective in both the bacterial and salvage pathways. Similar to other NAmPRTases, the KVP40 enzyme displayed ATPase activity indicative of energy coupling in the reaction mechanism. The NatV NMNATase activity was measured in a coupled reaction system demonstrating NAD biosynthesis from nicotinamide, phosphoribosyl pyrophosphate, and ATP. The NatV Nudix hydrolase domain was also shown to be active, with preferred substrates of ADP-ribose, NAD , and NADH. Expression analysis using reverse transcription-quantitative PCR (qRT-PCR) and enzyme assays of infected cells demonstrated and transcription during the early and delayed-early periods of infection when other KVP40 genes of nucleotide precursor metabolism are expressed. The distribution and phylogeny of NadV and NatV proteins among several large double-stranded DNA (dsDNA) myophages, and also those from some very large siphophages, suggest broad relevance of pyridine nucleotide scavenging in virus-infected cells. NAD biosynthesis presents another important metabolic resource control point by large, rapidly replicating dsDNA bacteriophages. T4-type bacteriophages enhance DNA precursor synthesis through reductive reactions that use NADH/NADPH as the electron donor and NAD for ADP-ribosylation of proteins involved in transcribing and translating the phage genome. We show here that phage KVP40 encodes a functional pyridine nucleotide scavenging pathway that is expressed during the metabolic period of the infection cycle. The pathway is conserved in other large, dsDNA phages in which the two genes, and , share an evolutionary history in their respective phage-host group.
[Mh] Termos MeSH primário: Bacteriófago T4/genética
Redes e Vias Metabólicas/genética
NAD/metabolismo
Piridinas/química
Vibrio parahaemolyticus/virologia
[Mh] Termos MeSH secundário: Escherichia coli/genética
Genômica
Nicotinamida-Nucleotídeo Adenililtransferase/genética
Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo
Nucleotídeos
Pirofosfatases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleotides); 0 (Pyridines); 0U46U6E8UK (NAD); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase); EC 3.6.1.- (Pyrophosphatases); EC 3.6.1.22 (NAD pyrophosphatase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171011
[Lr] Data última revisão:
171011
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170208
[St] Status:MEDLINE


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[PMID]:27984041
[Au] Autor:Bathke J; Fritz-Wolf K; Brandstädter C; Burkhardt A; Jortzik E; Rahlfs S; Becker K
[Ad] Endereço:Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, D-35392 Giessen, Germany.
[Ti] Título:Structural and Functional Characterization of Plasmodium falciparum Nicotinic Acid Mononucleotide Adenylyltransferase.
[So] Source:J Mol Biol;428(24 Pt B):4946-4961, 2016 Dec 04.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nicotinic acid mononucleotide adenylyltransferase (NaMNAT) is an indispensable enzyme for the synthesis of NAD and NAD phosphate. It catalyzes the adenylylation of nicotinic acid mononucleotide (NaMN) to yield nicotinic acid adenine dinucleotide (NaAD). Since NAD(H) and NAD phosphate(H) are essentially involved in metabolic and redox regulatory reactions, NaMNAT is an attractive drug target in the fight against bacterial and parasitic infections. Notably, NaMNAT of the malaria parasite Plasmodium falciparum possesses only 20% sequence identity with the homologous human enzyme. Here, we present for the first time the two X-ray structures of P. falciparum NaMNAT (PfNaMNAT)-in the product-bound state with NaAD and complexed with an α,ß-non-hydrolizable ATP analog-the structures were determined to a resolution of 2.2Å and 2.5Å, respectively. The overall architecture of PfNaMNAT was found to be more similar to its bacterial homologs than its human counterparts although the PPHK motif conserved in bacteria is missing. Furthermore, PfNaMNAT possesses two cysteine residues within the active site that have not been described for any other NaMNATase so far and are likely to be involved in redox regulation of PfNaMNAT activity. Enzymatic studies and surface plasmon resonance data reveal that PfNaMNAT is capable of utilizing NaMN and nicotinamide mononucleotide with a slight preference for NaMN. Surprisingly, a comparison with the active site of Escherichia coli NaMNAT showed very similar architectures, despite different substrate preferences.
[Mh] Termos MeSH primário: Nicotinamida-Nucleotídeo Adenililtransferase/química
Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo
Plasmodium falciparum/enzimologia
[Mh] Termos MeSH secundário: Domínio Catalítico
Cristalografia por Raios X
Cisteína/química
Cisteína/metabolismo
Modelos Moleculares
NAD/metabolismo
NADP/metabolismo
Mononucleotídeo de Nicotinamida/análogos & derivados
Mononucleotídeo de Nicotinamida/metabolismo
Conformação Proteica
Especificidade por Substrato
Ressonância de Plasmônio de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0U46U6E8UK (NAD); 1094-61-7 (Nicotinamide Mononucleotide); 321-02-8 (nicotinate mononucleotide); 53-59-8 (NADP); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase); EC 2.7.7.18 (nicotinic acid mononucleotide adenylyltransferase); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE


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[PMID]:27923046
[Au] Autor:Chen L; Nye DM; Stone MC; Weiner AT; Gheres KW; Xiong X; Collins CA; Rolls MM
[Ad] Endereço:Huck Institutes of the Life Sciences, and Biochemistry and Molecular Biology,The Pennsylvania State University, University Park, Pennsylvania, United States of America.
[Ti] Título:Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.
[So] Source:PLoS Genet;12(12):e1006503, 2016 Dec.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Axon injury can lead to several cell survival responses including increased stability and axon regeneration. Using an accessible Drosophila model system, we investigated the regulation of injury responses and their relationship. Axon injury stabilizes the rest of the cell, including the entire dendrite arbor. After axon injury we found mitochondrial fission in dendrites was upregulated, and that reducing fission increased stabilization or neuroprotection (NP). Thus axon injury seems to both turn on NP, but also dampen it by activating mitochondrial fission. We also identified caspases as negative regulators of axon injury-mediated NP, so mitochondrial fission could control NP through caspase activation. In addition to negative regulators of NP, we found that nicotinamide mononucleotide adenylyltransferase (Nmnat) is absolutely required for this type of NP. Increased microtubule dynamics, which has previously been associated with NP, required Nmnat. Indeed Nmnat overexpression was sufficient to induce NP and increase microtubule dynamics in the absence of axon injury. DLK, JNK and fos were also required for NP. Because NP occurs before axon regeneration, and NP seems to be actively downregulated, we tested whether excessive NP might inhibit regeneration. Indeed both Nmnat overexpression and caspase reduction reduced regeneration. In addition, overexpression of fos or JNK extended the timecourse of NP and dampened regeneration in a Nmnat-dependent manner. These data suggest that NP and regeneration are conflicting responses to axon injury, and that therapeutic strategies that boost NP may reduce regeneration.
[Mh] Termos MeSH primário: Axônios/metabolismo
Drosophila melanogaster/genética
Nicotinamida-Nucleotídeo Adenililtransferase/genética
Degeneração Walleriana/genética
[Mh] Termos MeSH secundário: Animais
Axônios/patologia
Caspases/biossíntese
Caspases/genética
Dendritos/metabolismo
Dendritos/patologia
Proteínas de Drosophila/biossíntese
Proteínas de Drosophila/genética
Drosophila melanogaster/crescimento & desenvolvimento
Seres Humanos
MAP Quinase Quinase 4/biossíntese
MAP Quinase Quinase 4/genética
Microtúbulos/genética
Microtúbulos/patologia
Dinâmica Mitocondrial/genética
Neurônios/metabolismo
Neurônios/patologia
Fármacos Neuroprotetores/metabolismo
Nicotinamida-Nucleotídeo Adenililtransferase/antagonistas & inibidores
Nicotinamida-Nucleotídeo Adenililtransferase/biossíntese
RNA Interferente Pequeno/genética
Degeneração Walleriana/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Neuroprotective Agents); 0 (RNA, Small Interfering); 0 (kayak protein, Drosophila); EC 2.7.12.2 (MAP Kinase Kinase 4); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase); EC 3.4.22.- (Caspases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170509
[Lr] Data última revisão:
170509
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161207
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006503



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