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NAD+ AND nicotinic acid

Timothy J Brickman, Sandra K Armstrong
The classical Bordetella species use amino acids as carbon sources and can catabolize organic acids and tricarboxylic acid cycle intermediates. They are also auxotrophic for nicotinamide adenine dinucleotide (NAD) pathway precursors such as nicotinic acid. Bordetellae have a putative nicotinate catabolism gene locus highly similar to that characterized in Pseudomonas putida KT2440. This study determined the distribution of the nic genes among Bordetella species and analyzed the regulation of this nicotinic acid degradation system...
February 27, 2018: Molecular Microbiology
James B Kirkland, Mirella L Meyer-Ficca
Nicotinic acid and nicotinamide, collectively referred to as niacin, are nutritional precursors of the bioactive molecules nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are important cofactors for most cellular redox reactions, and as such are essential to maintain cellular metabolism and respiration. NAD also serves as a cosubstrate for a large number of ADP-ribosylation enzymes with varied functions. Among the NAD-consuming enzymes identified to date are important genetic and epigenetic regulators, e...
2018: Advances in Food and Nutrition Research
Trevor Croft, Christol James Theoga Raj, Michelle Salemi, Brett S Phinney, Su-Ju Lin
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite participating in cellular redox chemistry and signaling, and the complex regulation of NAD+ metabolism is not yet fully understood. To investigate this, we established a NAD+-intermediate specific reporter system to identify factors required for salvage of metabolically-linked nicotinamide (NAM) and nicotinic acid (NA). Mutants lacking components of the NatB complex, NAT3 and MDM20, appeared as hits in this screen. NatB is an Nα-terminal-acetyltransferase responsible for acetylation of the amino terminus of specific Met-retained peptides...
January 9, 2018: Journal of Biological Chemistry
Nicolas Diguet, Samuel A J Trammell, Cynthia Tannous, Robin Deloux, Jérôme Piquereau, Nathalie Mougenot, Anne Gouge, Mélanie Gressette, Boris Manoury, Jocelyne Blanc, Marie Breton, Jean-François Decaux, Gareth Lavery, István Baczkó, Joffrey Zoll, Anne Garnier, Zhenlin Li, Charles Brenner, Mathias Mericskay
Background -Myocardial metabolic impairment is a major feature in chronic heart failure (HF). As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, NAD+ is emerging as a metabolic target in a number of diseases including HF. Little is known on mechanisms regulating homeostasis of NAD+ in the failing heart. Methods -To explore possible alterations of NAD+ homeostasis in the failing heart, we quantified expression of NAD+ biosynthetic enzymes in human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by SRF transcription factor depletion in the heart (SRFHKO ) or of cardiac hypertrophy triggered by transverse aorta constriction (TAC)...
December 7, 2017: Circulation
Kenji Konishi, Shigeru Ueda, Miki Kawano, Susumu Osawa, Tomohiro Tamura, Eisaku Hokazono, Yuzo Kayamori, Shin-Ichi Sakasegawa
Herein, we describe a novel enzymatic cycling method to measure nicotinamide mononucleotide (NMN) or nicotinic acid mononucleotide (NaMN), which are precursors of NAD biosynthesis. A gene encoding an NMN adenylyltransferase (NMNAT, EC homologue was identified in Thermus thermophilus HB8. The gene from T. thermophilus (TtNMNAT) was engineered for expression in Escherichia coli and the recombinant enzyme found to be stable, retaining full activity after incubation for 45 min at 70°C. The Km values for NMN and ATP were calculated to be 0...
November 23, 2017: Journal of Bioscience and Bioengineering
Jonathan Cole, Marie-Christine Guiot, Michel Gravel, Cynthia Bernier, Gordon C Shore, Anne Roulston
Tumor cells are particularly dependent on NAD(+) due to higher rates of metabolism, DNA synthesis and repair. Nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) inhibit NAD(+) biosynthesis and represent promising new anti-cancer agents. However, clinical efficacy has been limited by toxicities demonstrating the need for drug combinations to broaden the therapeutic index. One potential combination involves niacin/NAMPTi co-administration. Niacin can rescue NAD(+) biosynthesis through a parallel pathway that depends on nicotinic acid phosphoribosyltransferase (NAPRT) expression...
September 29, 2017: Oncotarget
Genshi Zhao, Colin F Green, Yu-Hua Hui, Lourdes Prieto, Robert Shepard, Sucai Dong, Tao Wang, Bo Tan, Xueqian Gong, Lisa Kays, Robert L Johnson, Wenjuan Wu, Shobha Bhattachar, Miriam Del Prado, James R Gillig, Maria-Carmen Fernandez, Ken D Roth, Sean Buchanan, Ming-Shang Kuo, Sandaruwan Geeganage, Timothy P Burkholder
NAMPT, an enzyme essential for NAD+ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity...
December 2017: Molecular Cancer Therapeutics
S Takao, W Chien, V Madan, D-C Lin, L-W Ding, Q-Y Sun, A Mayakonda, M Sudo, L Xu, Y Chen, Y-Y Jiang, S Gery, M Lill, E Park, W Senapedis, E Baloglu, M Müschen, H P Koeffler
Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism...
September 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Elisabeth F P Peterse, Brendy E W M van den Akker, Bertine Niessen, Jan Oosting, Johnny Suijker, Yvonne de Jong, Erik H J Danen, Anne-Marie Cleton-Jansen, Judith V M G Bovée
Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the NAD+ synthesis pathway. Chondrosarcoma is a malignant cartilage forming bone tumor, in which mutations altering isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) activity have been identified as potential driver mutations. Vulnerability for NAD+ depletion has been reported for IDH1/2 -mutant cells. Here, the potency of NAMPT inhibitors as a treatment of chondrosarcoma was explored...
December 2017: Molecular Cancer Research: MCR
Rubén Zapata-Pérez, Ana-Belén Martínez-Moñino, Antonio-Ginés García-Saura, Juana Cabanes, Hideto Takami, Álvaro Sánchez-Ferrer
Nicotinamidases are amidohydrolases that convert nicotinamide into nicotinic acid, contributing to NAD+ homeostasis in most organisms. In order to increase the number of nicotinamidases described to date, this manuscript characterizes a nicotinamidase obtained from a metagenomic library fosmid clone (JFF054_F02) obtained from a geothermal water stream microbial mat community in a Japanese epithermal mine. The enzyme showed an optimum temperature of 90°C, making it the first hyperthermophilic bacterial nicotinamidase to be characterized, since the phylogenetic analysis of this fosmid clone placed it in a clade of uncultured geothermal bacteria...
2017: PloS One
Zhilong Wang, Yanhang Gao, Chao Zhang, Haiming Hu, Dongwei Guo, Yi Xu, Qiuping Xu, Weihong Zhang, Sisi Deng, Pingyun Lv, Yan Yang, Yanhua Ding, Qingquan Li, Changjiang Weng, Xinwen Chen, Sitang Gong, Hairong Chen, Junqi Niu, Hong Tang
HCV infection can decrease NAD(+)/NADH ratio, which could convert lipid metabolism to favor HCV replication. In hepatocytes, quinolinate phosphoribosyl transferase (QPRT) catabolizes quinolinic acid (QA) to nicotinic acid mononucleotide (NAMN) for de novo NAD synthesis. However, whether and how HCV modulates QPRT hence the lipogenesis is unknown. In this work, we found QPRT was reduced significantly in livers of patients or humanized C/O(Tg) mice with persistent HCV infection. Mechanistic studies indicated that HCV NS3/4A promoted proteasomal degradation of QPRT through Smurf2, an E3 ubiquitin-protein ligase, in Huh7...
July 19, 2017: Scientific Reports
Odile Bouvet, Emmanuelle Bourdelier, Jeremy Glodt, Olivier Clermont, Erick Denamur
Isolates of Escherichia coli, except Shigella, are generally prototrophic; they do not require any growth factors to grow in mineral medium. However, a nicotinic acid requirement is common among B2 phylogroup STc95 O18 E. coli clone strains. Nicotinic acid is a precursor of nicotinamide adenine dinucleotide (NAD), an essential molecule that plays central role in cellular metabolism. The defect in NAD synthesis of these strains is due to alterations in de novo biosynthesis pathway nadB gene. Here, by studying growth on minimal medium with glycolytic (glucose) or gluconeogenic (pyruvate or succinate) substrates as the carbon supply in a large panel of E...
June 2017: Microbiology
Antje Bruckbauer, Jheelam Banerjee, Quiang Cao, Xin Cui, Jia Jing, Lin Zha, Fenfen Li, Bingzhong Xue, Hang Shi, Michael B Zemel
BACKGROUND/AIMS: Nicotinic acid (NA), a lipid-lowering drug, serves as a source of NAD(+), the cofactor for Sirt1. Leucine (Leu) stimulates the AMPK/Sirt1 axis and amplifies the effects of other AMPK/Sirt1 activating compounds. Therefore, we tested the interactive effects of leucine and low dose NA on AMPK/Sirt1 signaling and downstream effects of lipid metabolism in cell culture, C. elegans and mice. METHODS: LDL-receptor knockout mice were fed an atherogenic Western diet supplemented with leucine (24 g/kg diet) and sub-therapeutic NA combinations (50 mg/kg diet and 250 mg/kg diet) or low therapeutic NA (1000 mg/kg diet) for 8 weeks to evaluate markers of hyperlipidemia and atherosclerosis...
2017: American Journal of Cardiovascular Disease
Wei Li, Fengxia Zhang, Ranran Wu, Lijia Jia, Guosheng Li, Yalong Guo, Cuimin Liu, Guodong Wang
The Preiss-Handler pathway, which salvages nicotinate (NA) for NAD synthesis, is an indispensable biochemical pathway in land plants. Various NA conjugations (mainly methylation and glycosylation) have been detected and have long been proposed for NA detoxification in plants. Previously, we demonstrated that NA O-glucosylation functions as a mobilizable storage form for NAD biosynthesis in the Brassicaceae. However, little is known about the functions of other NA conjugations in plants. In this study, we first found that N-methylnicotinate is a ubiquitous NA conjugation in land plants...
July 2017: Plant Physiology
Francesco Piacente, Irene Caffa, Silvia Ravera, Giovanna Sociali, Mario Passalacqua, Valerio G Vellone, Pamela Becherini, Daniele Reverberi, Fiammetta Monacelli, Alberto Ballestrero, Patrizio Odetti, Antonia Cagnetta, Michele Cea, Aimable Nahimana, Michel Duchosal, Santina Bruzzone, Alessio Nencioni
In the last decade, substantial efforts have been made to identify NAD(+) biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD(+) production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD(+)-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature...
July 15, 2017: Cancer Research
Xueying Wang, Yongjin J Zhou, Lei Wang, Wujun Liu, Yuxue Liu, Chang Peng, Zongbao K Zhao
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 Escherichia coli, NAD de novo biosynthesis depends on the protein NadD-catalyzed adenylylation of NaMN to nicotinic acid adenine dinucleotide (NaAD), followed by NAD synthase-catalyzed amidation...
July 1, 2017: Applied and Environmental Microbiology
Ana Belén Martínez-Moñino, Rubén Zapata-Pérez, Antonio Ginés García-Saura, Fernando Gil-Ortiz, Manuela Pérez-Gilabert, Álvaro Sánchez-Ferrer
NAD+ has emerged as a crucial element in both bioenergetic and signaling pathways since it acts as a key regulator of cellular and organismal homeostasis. Among the enzymes involved in its recycling, nicotinamide mononucleotide (NMN) deamidase is one of the key players in the bacterial pyridine nucleotide cycle, where it catalyzes the conversion of NMN into nicotinic acid mononucleotide (NaMN), which is later converted to NAD+ in the Preiss-Handler pathway. The biochemical characteristics of bacterial NMN deamidases have been poorly studied, although they have been investigated in some firmicutes, gamma-proteobacteria and actinobacteria...
2017: PloS One
Ming-Jia Yu, Shi-Lu Chen
Lactate racemase (LarA), a new nickel enzyme discovered recently, catalyzes the racemization between d- and l-lactates with a novel nickel pincer cofactor (Ni-PTTMN) derived from nicotinic acid. In this study, by using DFT and a 200-atom active-site model, LarA is revealed to employ a modified proton-coupled hydride-transfer mechanism in which a hydride is transferred to a cofactor pyridine carbon from the substrate α-carbon along with proton transfer from the substrate hydroxy group to a histidine, and then moved back from the opposite side...
April 4, 2017: Chemistry: a European Journal
Muhammad Afzal, Oscar P Kuipers, Sulman Shafeeq
NAD (Nicotinamide Adenine Dinucleotide) biosynthesis is vital for bacterial physiology and plays an important role in cellular metabolism. A naturally occurring vitamin B complex, niacin (nicotinic acid), is a precursor of coenzymes NAD and NADP. Here, we study the impact of niacin on global gene expression of Streptococcus pneumoniae D39 and elucidate the role of NiaR as a transcriptional regulator of niaX, nadC, and pnuC. Transcriptome comparison of the D39 wild-type grown in chemically defined medium (CDM) with 0 to 10 mM niacin revealed elevated expression of various genes, including niaX, nadC, pnuC, fba, rex, gapN, pncB, gap, adhE, and adhB2 that are putatively involved in the transport and utilization of niacin...
2017: Frontiers in Cellular and Infection Microbiology
Kathrin Weidele, Sascha Beneke, Alexander Bürkle
NAD+ is an essential cofactor for enzymes catalyzing redox-reactions as well as an electron carrier in energy metabolism. Aside from this, NAD+ consuming enzymes like poly(ADP-ribose) polymerases and sirtuins are important regulators involved in chromatin-restructuring processes during repair and epigenetics/transcriptional adaption. In order to replenish cellular NAD+ levels after cleavage, synthesis starts from precursors such as nicotinamide, nicotinamide riboside or nicotinic acid to match the need for this essential molecule...
April 2017: DNA Repair
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