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Bharathkumar Inturi, Gurubasavaraj V Pujar, Madhusudhan N Purohit
Mycobacterium tuberculosis enoyl-ACP reductase (InhA) has been validated as a promising target for antitubercular agents. Isoniazid (INH), the most prescribed drug to treat tuberculosis (TB), inhibits a NADH-dependent InhA that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. It is a pro-drug that needs activation to form the inhibitory INH-NAD adduct by KatG coding for catalase-peroxidase. The INH resistance of M. tuberculosis is caused by mutations in KatG, which may lead to multidrug-resistant TB (MDR-TB)...
October 24, 2016: Archiv der Pharmazie
Brett A Beaupre, Joseph V Roman, Matthew R Hoag, Kathleen M Meneely, Nicholas R Silvaggi, Audrey L Lamb, Graham R Moran
Renalase catalyzes the oxidation of isomers of β-NAD(P)H that carry the hydride in the 2 or 6 positions of the nicotinamide base to form β-NAD(P)(+). This activity is thought to alleviate inhibition of multiple β-NAD(P)-dependent enzymes of primary and secondary metabolism by these isomers. Here we present evidence for a variety of ligand binding phenomena relevant to the function of renalase. We offer evidence of the potential for primary metabolism inhibition with structures of malate dehydrogenase and lactate dehydrogenase bound to the 6-dihydroNAD isomer...
October 18, 2016: Archives of Biochemistry and Biophysics
Igor Florez-Sarasa, Ko Noguchi, Wagner Araujo, Ana Garcia-Nogales, Alisdair R Fernie, Jaume Flexas, Miquel Ribas-Carbo
The cyclic electron flow around photosystem I (CEF-PSI) increases ATP/NADPH production in the chloroplast acting as an energy balance mechanism. Higher export of reducing power from the chloroplast in CEF-PSI mutants has been correlated with higher mitochondrial alternative oxidase (AOX) capacity and protein amount under high light (HL) conditions. However, in vivo measurements of AOX activity are still required to confirm the exact role of AOX on dissipating the excess of reductant power from the chloroplast...
October 19, 2016: Plant Physiology
Kazuki Kawahara, Shinya Yonogi, Ryota Munetomo, Hiroya Oki, Takuya Yoshida, Yuko Kumeda, Shigeaki Matsuda, Toshio Kodama, Tadayasu Ohkubo, Tetsuya Iida, Shota Nakamura
Binary enterotoxin of Clostridium perfringens (BEC), consisting of the components BECa and BECb, was recently identified as a novel enterotoxin produced by C. perfringens that causes acute gastroenteritis in humans. Although the detailed mechanism of cell intoxication by BEC remains to be defined, BECa shows both NAD(+)-glycohydrolase and actin ADP-ribosyltransferase activities in the presence of NAD(+). In this study, we determined the first crystal structure of BECa in its apo-state and in complex with NADH...
October 14, 2016: Biochemical and Biophysical Research Communications
Dan Y Gui, Lucas B Sullivan, Alba Luengo, Aaron M Hosios, Lauren N Bush, Nadege Gitego, Shawn M Davidson, Elizaveta Freinkman, Craig J Thomas, Matthew G Vander Heiden
Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin's anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis...
October 12, 2016: Cell Metabolism
Gina L O'Grady, Heather A Best, Tamar E Sztal, Vanessa Schartner, Myriam Sanjuan-Vazquez, Sandra Donkervoort, Osorio Abath Neto, Roger Bryan Sutton, Biljana Ilkovski, Norma Beatriz Romero, Tanya Stojkovic, Jahannaz Dastgir, Leigh B Waddell, Anne Boland, Ying Hu, Caitlin Williams, Avnika A Ruparelia, Thierry Maisonobe, Anthony J Peduto, Stephen W Reddel, Monkol Lek, Taru Tukiainen, Beryl B Cummings, Himanshu Joshi, Juliette Nectoux, Susan Brammah, Jean-François Deleuze, Viola Oorschot Ing, Georg Ramm, Didem Ardicli, Kristen J Nowak, Beril Talim, Haluk Topaloglu, Nigel G Laing, Kathryn N North, Daniel G MacArthur, Sylvie Friant, Nigel F Clarke, Robert J Bryson-Richardson, Carsten G Bönnemann, Jocelyn Laporte, Sandra T Cooper
This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase...
September 28, 2016: American Journal of Human Genetics
Krisztina Marosi, Sang Woo Kim, Keelin Moehl, Morten Scheibye-Knudsen, Aiwu Cheng, Roy Cutler, Simonetta Camandola, Mark P Mattson
During fasting and vigorous exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3-hydroxybutyrate (3OHB) occurs. Studies have shown that 3OHB can protect neurons against excitotoxicity and oxidative stress, but the underlying mechanisms are unclear. Neurons maintained in the presence of 3OHB exhibited increased oxygen consumption and ATP production, and an elevated NAD+/NADH ratio. We found that 3OHB metabolism increases mitochondrial respiration which drives changes in expression of brain derived neurotrophic factor (BDNF) in cultured cerebral cortical neurons...
October 14, 2016: Journal of Neurochemistry
Mingguang Yan, Weibing Yin, Xiao Fang, Jianjun Guo, Hong Shi
NADH oxidases (NOXs) catalyzing the oxidation of NADH to yield NAD(+) and H2O, H2O2, or both play an important role in protecting organisms from oxidative stress and maintaining the balance of NAD(+)/NADH. A gene encoding NOX was identified from Methanobrevibacter smithii (NOX-ms), the predominant archaeon in the human gut ecosystem. Subsequent analyses showed that it is an FAD-containing protein with a subunit molecular mass of 48 kDa. NOX-ms was purified to homogeneity after expression in Escherichia coli NOX-ms catalyzed the oxidization of NADH and converted O2 to H2O with an optimal pH of 7...
October 13, 2016: Bioscience Reports
Tomoki Sato, Yuma Yoshida, Akihito Morita, Nobuko Mori, Shinji Miura
BACKGROUND: Glucose is used as an energy source in many organs and obtained from dietary carbohydrates. However, when the external energy supply is interrupted, e.g., during fasting, carbohydrates preserved in the liver and glycogenic precursors derived from other organs are used to maintain blood glucose levels. Glycerol and glycogenic amino acids derived from adipocytes and skeletal muscles are utilized as glycogenic precursors. Glycerol-3-phosphate dehydrogenase 1 (GPD1), an NAD(+)/NADH-dependent enzyme present in the cytosol, catalyzes the reversible conversion of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate (DHAP)...
November 2016: Metabolism: Clinical and Experimental
Reiko Sanokawa-Akakura, Shin Akakura, Siamak Tabibzadeh
Recent evidence suggests that hydrogen sulfide (H2S) has cytoprotective and anti-aging effects. However, the mechanisms for such properties are not fully understood. Here, we show that the expression of the main H2S producing enzyme, CBS, and production of H2S are coordinately diminished in replicative senescent adult human dermal fibroblasts. The reduced production of H2S falls within the same time-frame that the hallmarks of replicative senescence appear including accumulation of SA-β-Gal, enhanced expression of p16, p21, and RRM2B while the expression of RRM2, hTERT, SIRT1, NAMPT, and NAD/NADH ratio all fall...
2016: PloS One
Sachin V Surve, Brian C Jensen, Meredith Heestand, Muriel Mazet, Terry K Smith, Frédéric Bringaud, Marilyn Parsons, Achim Schnaufer
In the slender bloodstream form, Trypanosoma brucei mitochondria are repressed for many functions. Multiple components of mitochondrial complex I, NADH:ubiquinone oxidoreductase, are expressed in this stage, but electron transfer through complex I is not essential. Here we investigate the role of the parasite's second NADH:ubiquinone oxidoreductase, NDH2, which is composed of a single subunit that also localizes to the mitochondrion. While inducible knockdown of NDH2 had a modest growth effect in bloodstream forms, NDH2 null mutants, as well as inducible knockdowns in a complex I deficient background, showed a greater reduction in growth...
October 4, 2016: Molecular and Biochemical Parasitology
Hongyun Nie, Maiqian Nie, Ting Xiao, Yan Wang, Xiaoting Tian
For further understanding of the roles of small organic acids commonly produced during alkane degradation, glutaric acid was found to be effective for promoting hexadecane degradation by P. aeruginosa NY3. Our results demonstrated that the synchronous metabolism of glutaric acid could increase both the growth rates and hexadecane degradation ability of P. aeruginosa NY3. Glutaric acid was proved to be able to increase the ratios of the concentrations of NAD(+) and NADH inside strain NY3 cells, and subsequently accelerated cell growth rates through improving electron respiration rates...
October 4, 2016: Science of the Total Environment
Hideki Ohtsu, Sho Fujii, Kiyoshi Tsuge, Koji Tanaka
A four-electron-reduced ruthenium(ii) NADH-type complex, [Ru(bbnpH4)(CO)2Cl](PF6) (bbnpH4 = 2,2'-(4-(tert-butyl)pyridine-2,6-diyl)bis(5,10-dihydrobenzo[b][1,5]naphthyridine)), has been successfully synthesized by mixing an NAD(+)-type ligand, bbnp (bbnp = 2,2'-(4-(tert-butyl)pyridine-2,6-diyl)bis(benzo[b][1,5]naphthyridine)), and [Ru(CO)2Cl2] under moderate water-gas-shift reaction conditions, which has been fully characterized by single-crystal X-ray structure analysis, ESI-TOF mass spectrometry, and NMR spectroscopy...
October 18, 2016: Dalton Transactions: An International Journal of Inorganic Chemistry
Jorgelindo da Veiga Moreira, Minoo Hamraz, Mohammad Abolhassani, Erwan Bigan, Sabine Pérès, Loïc Paulevé, Marcel Levy Nogueira, Jean-Marc Steyaert, Laurent Schwartz
To better understand the energetic status of proliferating cells, we have measured the intracellular pH (pHi) and concentrations of key metabolites, such as adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP) in normal and cancer cells, extracted from fresh human colon tissues. Cells were sorted by elutriation and segregated in different phases of the cell cycle (G0/G1/S/G2/M) in order to study their redox (NAD, NADP) and bioenergetic (ATP, pHi) status...
October 3, 2016: Metabolites
Liang Tian, Jonathan Lo, Xiongjun Shao, Tianyong Zheng, Daniel G Olson, Lee R Lynd
: Ferredoxin:NAD(+) oxidoreductase (NADH-FNOR) catalyzes the transfer of electrons from reduced ferredoxin to NAD(+) This enzyme has been hypothesized to be the main enzyme responsible for ferredoxin oxidization in the NADH-based ethanol pathway in Thermoanaerobacterium saccharolyticum, however, the corresponding gene has not yet been identified. Here, we identified the Tsac_1705 protein as a candidate FNOR based on the homology of its functional domains. We then confirmed its activity in vitro with a ferredoxin-based FNOR assay...
September 30, 2016: Applied and Environmental Microbiology
Marta Delgado-Camprubi, Noemi Esteras, Marc Pm Soutar, Helene Plun-Favreau, Andrey Y Abramov
The Parkinson's disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD(+) levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain...
September 30, 2016: Cell Death and Differentiation
Rachel Cinco, Michelle A Digman, Enrico Gratton, Ulrike Luderer
Previous work characterizing ovarian bioenergetics has defined follicular metabolism by measuring metabolic byproducts in culture media. However, culture conditions perturb the native state of the follicle, and these methods do not distinguish between metabolism occurring within oocytes or granulosa cells. We applied the phasor approach to fluorescent lifetime imaging microscopy (Phasor FLIM) at 740 nm 2-photon excitation to examine the spatial distribution of free and protein-bound nicotinamide adenine dinucleotide hydride (NADH) during primordial through preovulatory stages of follicular development in fresh ex vivo murine neonatal and gonadotropin stimulated pre-pubertal ovaries...
September 28, 2016: Biology of Reproduction
Xinchi Shi, Yanan Zou, Yong Chen, Cheng Zheng, Hanjie Ying
Redox homeostasis is fundamental to the maintenance of metabolism. Redox imbalance can cause oxidative stress, which affects metabolism and growth. Water-forming NADH oxidase regulates the redox balance by oxidizing cytosolic NADH to NAD(+), which relieves cytosolic NADH accumulation through rapid glucose consumption in Saccharomyces cerevisiae, thus decreasing the production of the by product glycerol in industrial ethanol production. Here, we studied the effects of overexpression of a water-forming NADH oxidase from Lactococcus lactis on the stress response of S...
2016: Frontiers in Microbiology
Tatsufumi Goto, Kotomi Sugawara, Shigeyoshi Nakamura, Shun-Ichi Kidokoro, Hideki Wakui, Wataru Nunomura
Lactate dehydrogenase (LDH) is a glycolytic enzyme that catalyzes the final step of glycolysis and produces NAD(+). In somatic cells, LDH forms homotetramers and heterotetramers that are encoded by two different genes: LDHA (skeletal muscle type, M) and LDHB (heart type, H). Analysis of LDH isozymes is important for understanding the physiological role of homotetramers and heterotetramers and for optimizing inhibition of their enzymatic activity as it may result in distinct effects. Previously, we reported that hydroxychloroquine (HCQ) inhibited LDH activity, but we did not examine isozyme specificity...
October 28, 2016: Biochemical and Biophysical Research Communications
Robin A de Graaf, Henk M De Feyter, Peter B Brown, Terence W Nixon, Douglas L Rothman, Kevin L Behar
PURPOSE: To develop (1) H-based MR detection of nicotinamide adenine dinucleotide (NAD(+) ) in the human brain at 7T and validate the (1) H results with NAD(+) detection based on (31) P-MRS. METHODS: (1) H-MR detection of NAD(+) was achieved with a one-dimensional double-spin-echo method on a slice parallel to the surface coil transceiver. Perturbation of the water resonance was avoided through the use of frequency-selective excitation. (31) P-MR detection of NAD(+) was performed with an unlocalized pulse-acquire sequence...
September 26, 2016: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
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