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Diana Milena Sánchez-Lancheros, Luis Fernando Ospina-Giraldo, María Helena Ramírez-Hernández
Nicotinamide/nicotinate adenine dinucleotide (NAD+/NaAD) performs essential functions in cell metabolism and energy production due to its redox properties. The nicotinamide/nicotinate mononucleotide adenylyltransferase (NMNAT, EC enzyme catalyses the key step in the biosynthesis of NAD+. Previously, the enzyme NMNAT was identified in Trypanosoma cruzi (TcNMNAT), a pathogenic agent with epidemiological importance in Latin America. To continue with the functional characterisation of this enzyme, its subcellular location and its possible post-translational modifications were examined in this study...
October 24, 2016: Memórias do Instituto Oswaldo Cruz
Erik S Musiek, David D Xiong, Tirth Patel, Yo Sasaki, Yinong Wang, Adam Q Bauer, Risham Singh, Samantha L Finn, Joseph P Culver, Jeffrey Milbrandt, David M Holtzman
OBJECTIVE: The nicotinamide-nucleotide adenylyltransferase protein Nmnat1 is a potent inhibitor of axonal degeneration in models of acute axonal injury. Hyperphosphorylation and aggregation of the microtubule-associated protein Tau are associated with neurodegeneration in Alzheimer's Disease and other disorders. Previous studies have demonstrated that other Nmnat isoforms can act both as axonoprotective agents and have protein chaperone function, exerting protective effects in drosophila and mouse models of tauopathy...
June 2016: Annals of Clinical and Translational Neurology
Ji H Park, Aaron Long, Katrina Owens, Tibor Kristian
Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor for multiple cellular metabolic reactions and has a central role in energy production. Brain ischemia depletes NAD(+) pools leading to bioenergetics failure and cell death. Nicotinamide mononucleotide (NMN) is utilized by the NAD(+) salvage pathway enzyme, nicotinamide adenylyltransferase (Nmnat) to generate NAD(+). Therefore, we examined whether NMN could protect against ischemic brain damage. Mice were subjected to transient forebrain ischemia and treated with NMN or vehicle at the start of reperfusion or 30min after the ischemic insult...
November 2016: Neurobiology of Disease
Chunhui Cui, Jia Qi, Quanwen Deng, Rihong Chen, Duanyang Zhai, Jinlong Yu
Colorectal cancer (CRC) is one of the most common cancers all over the world. It is essential to search for more effective diagnostic and therapeutic methods for CRC. Abnormal nicotinamide adenine dinucleotide (NAD) metabolism has been considered as a characteristic of cancer cells. In this study, nicotinamide mononucleotide adenylyl transferases (NMNATs) as well as p53-mediated cancer signaling pathways were investigated in patients with colorectal cancer. The CRC tissues and adjacent normal tissues were obtained from 95 untreated colorectal cancer patients and were stained for expression of nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) and p53...
2016: BioMed Research International
Matthew J Geden, Mohanish Deshmukh
Axon degeneration is an essential part of development, plasticity, and injury response and has been primarily studied in mammalian models in three contexts: 1) Axotomy-induced Wallerian degeneration, 2) Apoptosis-induced axon degeneration (axon apoptosis), and 3) Axon pruning. These three contexts dictate engagement of distinct pathways for axon degeneration. Recent advances have identified the importance of SARM1, NMNATs, NAD+ depletion, and MAPK signaling in axotomy-induced Wallerian degeneration. Interestingly, apoptosis-induced axon degeneration and axon pruning have many shared mechanisms both in signaling (e...
August 2016: Current Opinion in Neurobiology
Rong-Mei Zhou, Yi Shen, Jin Yao, Hong Yang, Kun Shan, Xiu-Miao Li, Qin Jiang, Biao Yan
BACKGROUND/AIMS: Retinal neurodegeneration is an early event in the pathological process of diabetic retinopathy (DR). Retinal ganglion cell (RGC) injury is an important pathological feature during neurodegenerative process. Protecting RGCs from high glucose-induced injury is a promising strategy for delaying or hindering diabetes mellitus-related retinal neuropathy. This study aims to investigate the role of Nmnat1, an enzyme which catalyzes a key step in the biosynthesis of nicotinamide adenine dinucleotide (NAD), in high glucose-induced RGC injury...
2016: Cellular Physiology and Biochemistry
Jyothi Padiadpu, Madhulika Mishra, Eshita Sharma, Uchurappa Mala, Kumar Somasundaram, Nagasuma Chandra
The biosynthesis of NAD constitutes an important metabolic module in the cell, since NAD is an essential cofactor involved in several metabolic reactions. NAD concentrations are known to be significantly increased in several cancers, particularly in glioma, consistent with the observation of up-regulation of several enzymes of the network. Modulating NAD biosynthesis in glioma is therefore an attractive therapeutic strategy. Here we report reconstruction of a biochemical network of NAD biosynthesis consisting of 22 proteins, 36 metabolites, and 86 parameters, tuned to mimic the conditions in glioma...
May 23, 2016: Journal of Chemical Information and Modeling
Annika L A Nichols, Ellen Meelkop, Casey Linton, Rosina Giordano-Santini, Robert K Sullivan, Alessandra Donato, Cara Nolan, David H Hall, Ding Xue, Brent Neumann, Massimo A Hilliard
Axonal degeneration is a characteristic feature of neurodegenerative disease and nerve injury. Here, we characterize axonal degeneration in Caenorhabditis elegans neurons following laser-induced axotomy. We show that this process proceeds independently of the WLD(S) and Nmnat pathway and requires the axonal clearance machinery that includes the conserved transmembrane receptor CED-1/Draper, the adaptor protein CED-6, the guanine nucleotide exchange factor complex Crk/Mbc/dCed-12 (CED-2/CED-5/CED-12), and the small GTPase Rac1 (CED-10)...
February 23, 2016: Cell Reports
Richard A Slivicki, Yousuf O Ali, Hui-Chen Lu, Andrea G Hohmann
Nicotinamide mononucleotide adenylyl transferases (NMNATs) are essential neuronal maintenance factors postulated to preserve neuronal function and protect against axonal degeneration in various neurodegenerative disease states. We used in vitro and in vivo approaches to assess the impact of NMNAT2 reduction on cellular and physiological functions induced by treatment with a vinca alkaloid (vincristine) and a taxane-based (paclitaxel) chemotherapeutic agent. NMNAT2 null (NMNAT2-/-) mutant mice die at birth and cannot be used to probe functions of NMNAT2 in adult animals...
2016: PloS One
Kai Ruan, Yi Zhu, Chong Li, Jennifer M Brazill, R Grace Zhai
Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved enzyme in the NAD synthetic pathway. It has also been identified as an effective and versatile neuroprotective factor. However, it remains unclear how healthy neurons regulate the dual functions of NMNAT and achieve self-protection under stress. Here we show that Drosophila Nmnat (DmNmnat) is alternatively spliced into two mRNA variants, RA and RB, which translate to protein isoforms with divergent neuroprotective capacities against spinocerebellar ataxia 1-induced neurodegeneration...
November 30, 2015: Nature Communications
Carlos H Niño, Nicolás Forero-Baena, Luis E Contreras, Diana Sánchez-Lancheros, Katherine Figarella, María H Ramírez
The intracellular parasite Trypanosoma cruzi is the aetiological agent of Chagas disease, a public health concern with an increasing incidence rate. This increase is due, among other reasons, to the parasite's drug resistance mechanisms, which require nicotinamide adenine dinucleotide (NAD+). Furthermore, this molecule is involved in metabolic and intracellular signalling processes necessary for the survival of T. cruzi throughout its life cycle. NAD+biosynthesis is performed by de novo and salvage pathways, which converge on the step that is catalysed by the enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT) (enzyme commission number: 2...
November 2015: Memórias do Instituto Oswaldo Cruz
Roland Pfoh, Emil F Pai, Vivian Saridakis
Nicotinamide mononucleotide adenylyltransferase (NMNAT) catalyzes the biosynthesis of NAD(+) and NaAD(+). The crystal structure of NMNAT from Methanobacterium thermoautotrophicum complexed with NAD(+) and SO4(2-) revealed the active-site residues involved in binding and catalysis. Site-directed mutagenesis was used to further characterize the roles played by several of these residues. Arg11 and Arg136 were implicated in binding the phosphate groups of the ATP substrate. Both of these residues were mutated to lysine individually...
October 2015: Acta Crystallographica. Section D, Biological Crystallography
Luis E Contreras, Rafik Neme, María H Ramírez
The progressive increase in Leishmania resistance to current control approaches prompts the need to develop therapeutic strategies based on comprehensive knowledge of the parasite's biology. The enzyme Nicotinamide Mononucleotide Adenylyltransferase (NMNAT, EC catalyzes the central step in nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, making it essential for the survival of all organisms. NAD(+) metabolism is related to the maintenance of several biochemical, cellular, and physiological processes; consequently, the characterization and analysis of the enzymes involved in its biosynthesis represent key steps in the development of control strategies...
November 2015: Protein Expression and Purification
Tian-Ying Xu, Sai-Long Zhang, Guo-Qiang Dong, Xin-Zhu Liu, Xia Wang, Xiao-Qun Lv, Qi-Jun Qian, Ruo-Yu Zhang, Chun-Quan Sheng, Chao-Yu Miao
Nicotinamide phosphoribosyltransferase (NAMPT) is a promising anticancer target. Using high throughput screening system targeting NAMPT, we obtained a potent NAMPT inhibitor MS0 (China Patent ZL201110447488.9) with excellent in vitro activity (IC50 = 9.87 ± 1.15 nM) and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure-activity relationship studies yielded several highly effective analogues. These inhibitors specifically bound NAMPT, rather than downstream NMNAT...
2015: Scientific Reports
Yunsheng Wang, Deming Zhao, Bo Pan, Zhiqi Song, Syed Zahid Ali Shah, Xiaomin Yin, Xiangmei Zhou, Lifeng Yang
Axonal degeneration is a hallmark of many neurodegenerative disorders including transmissible spongiform encephalopathies (TSE). However, the full complement of axonal degeneration triggers is not fully understood. In an in vitro prion model, we observed that treatment of rat spinal neurons with the prion peptide, PrP106-126, activated death receptor 6 (DR6, also known as TNFRSF21), caspase-6, caspase-3, and induced axonal degeneration. Knockdown of DR6 by siRNA blocked caspase-6 and caspase-3 activation and axonal degeneration...
August 2015: Journal of Molecular Neuroscience: MN
Jonathan Gilley, Giuseppe Orsomando, Isabel Nascimento-Ferreira, Michael P Coleman
SARM1 function and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) loss both promote axon degeneration, but their relative relationship in the process is unknown. Here, we show that NMNAT2 loss and resultant changes to NMNAT metabolites occur in injured SARM1-deficient axons despite their delayed degeneration and that axon degeneration specifically induced by NMNAT2 depletion requires SARM1. Strikingly, SARM1 deficiency also corrects axon outgrowth in mice lacking NMNAT2, independently of NMNAT metabolites, preventing perinatal lethality...
March 31, 2015: Cell Reports
Yasunari Munemasa, Yasushi Kitaoka
The role of autophagy in retinal ganglion cell (RGC) death is still controversial. Several studies focused on RGC body death, although the axonal degeneration pathway in the optic nerve has not been well documented in spite of evidence that the mechanisms of degeneration of neuronal cell bodies and their axons differ. Axonal degeneration of RGCs is a hallmark of glaucoma, and a pattern of localized retinal nerve fiber layer defects in glaucoma patients indicates that axonal degeneration may precede RGC body death in this condition...
July 2015: Progress in Retinal and Eye Research
Tanja S Zabka, Jatinder Singh, Preeti Dhawan, Bianca M Liederer, Jason Oeh, Mara A Kauss, Yang Xiao, Mark Zak, Tori Lin, Bobbi McCray, Nghi La, Trung Nguyen, Joseph Beyer, Cynthia Farman, Hirdesh Uppal, Peter S Dragovich, Thomas O'Brien, Deepak Sampath, Dinah L Misner
Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor, and hormone. NAMPT is of interest for oncology, because it catalyzes the rate-limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), which is considered a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. This manuscript describes NAMPT inhibitor-induced retinal toxicity that was identified in rodent safety studies...
March 2015: Toxicological Sciences: An Official Journal of the Society of Toxicology
Valerio Mori, Adolfo Amici, Francesca Mazzola, Michele Di Stefano, Laura Conforti, Giulio Magni, Silverio Ruggieri, Nadia Raffaelli, Giuseppe Orsomando
NAD plays essential redox and non-redox roles in cell biology. In mammals, its de novo and recycling biosynthetic pathways encompass two independent branches, the "amidated" and "deamidated" routes. Here we focused on the indispensable enzymes gating these two routes, i.e. nicotinamide mononucleotide adenylyltransferase (NMNAT), which in mammals comprises three distinct isozymes, and NAD synthetase (NADS). First, we measured the in vitro activity of the enzymes, and the levels of all their substrates and products in a number of tissues from the C57BL/6 mouse...
2014: PloS One
M Di Stefano, I Nascimento-Ferreira, G Orsomando, V Mori, J Gilley, R Brown, L Janeckova, M E Vargas, L A Worrell, A Loreto, J Tickle, J Patrick, J R M Webster, M Marangoni, F M Carpi, S Pucciarelli, F Rossi, W Meng, A Sagasti, R R Ribchester, G Magni, M P Coleman, L Conforti
NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration...
May 2015: Cell Death and Differentiation
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