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PubMed1988

Utilization of tryptophan, nicotinamide and nicotinic acid as precursors for nicotinamide nucleotide synthesis in isolated rat liver cells.

1. Incubation of isolated rat hepatocytes with nicotinamide or nicotinic acid showed that while both vitamers were taken up from the incubation medium, neither was utilized to any significant extent as a precursor of the nicotinamide nucleotide coenzymes, NAD and NADP, and neither was capable of preventing the loss of nucleotides that occurs on incubating the cells. 2. Incubation of hepatocytes with tryptophan showed that de novo synthesis from tryptophan permitted replacement of the nucleotides lost during incubation; at high concentrations of tryptophan there was an increase above the initial intracellular concentration of NAD(P). Incubation of hepatocytes with tryptophan also resulted in the formation and release from the cells of a considerable amount of niacin, as well as the two principal metabolities of NAD(P), N1-methyl nicotinamide and methyl pyridone carboxamide. 3. It is suggested that, in the liver, performed niacin is not utilized for nucleotide synthesis, and indeed the function of the liver appears to be synthesis of niacin from tryptophan, and its release for use by extrahepatic tissues that lack the pathway for de novo synthesis of nicotinamide nucleotides from tryptophan.

Animals↗

PubMed2003

Effects of hydrogen peroxide upon nicotinamide nucleotide metabolism in Escherichia coli: changes in enzyme levels and nicotinamide nucleotide pools and studies of the oxidation of NAD(P)H by Fe(III).

DNA is damaged in vivo by the Fenton reaction mediated by Fe2+ and cellular reductants such as NADH, which reduce Fe3+ to Fe2+ and allow the recycling of iron. To study the response of Escherichia coli to such cycling, the activities of several enzymes involved in nicotinamide nucleotide metabolism were measured following an H2O2 challenge. NADPH-dependent peroxidase, NADH/NADP+ transhydrogenase, and glucose-6-phosphate dehydrogenase were most strongly induced, increasing 2.5-3-fold. In addition, the cellular ratios of NADPH to NADH increased 6- or 92-fold 15 min after exposure to 0.5 or 5 mm H2O2, respectively. In vitro, NADH was oxidized by Fe3+ up to 16-fold faster than NADPH, despite their identical reduction potentials. To understand this rate difference, the interactions of Fe3+ and Ga3+ with NAD(P)H were examined by 1H, 13C, and 31P NMR spectroscopy. Association with NADH occurred primarily with adenine at N7 and the amino group, but for NADPH, strong metal interactions also occurred at the 2'-phosphate group. Interaction of M3+ (Fe3+ or Ga3+) with the adenine ring would bring it into close proximity to the redox-active nicotinamide ring in the folded form of NAD(P)H, but interaction of M3+ with the 2'-phosphate group would avoid this close contact. In addition, as determined by absorbance spectroscopy, the energy of the charge-transfer species was significantly higher for the Fe3+.NADPH complex than for the Fe3+.NADH complex. We therefore suggest that upon exposure to H2O2 the NADH pool is depleted, and NADPH, which is less reactive with Fe3+, functions as the major nicotinamide nucleotide reductant.

Enzymes↗

PubMed2001

NadN and e (P4) are essential for utilization of NAD and nicotinamide mononucleotide but not nicotinamide riboside in Haemophilus influenzae.

Haemophilus influenzae has an absolute requirement for NAD (factor V) because it lacks almost all the biosynthetic enzymes necessary for the de novo synthesis of that cofactor. Factor V can be provided as either nicotinamide adenosine dinucleotide (NAD), nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR) in vitro, but little is known about the source or the mechanism of uptake of these substrates in vivo. As shown by us earlier, at least two gene products are involved in the uptake of NAD, the outer membrane lipoprotein e (P4), which has phosphatase activity and is encoded by hel, and a periplasmic NAD nucleotidase, encoded by nadN. It has also been observed that the latter gene product is essential for H. influenzae growth on media supplemented with NAD. In this report, we describe the functions and substrates of these two proteins as they act together in an NAD utilization pathway. Data are provided which indicate that NadN harbors not only NAD pyrophosphatase but also NMN 5'-nucleotidase activity. The e (P4) protein is also shown to have NMN 5'-nucleotidase activity, recognizing NMN as a substrate and releasing NR as its product. Insertion mutants of nadN or deletion and site-directed mutants of hel had attenuated growth and a reduced uptake phenotype when NMN served as substrate. A hel and nadN double mutant was only able to grow in the presence of NR, whereas no uptake of NMN was observed.

Bacterial Outer Membrane Proteins↗

PubMed1975

Nicotinamide 3,N4-ethenocytosine dinucleotide, an analog of nicotinamide adenine dinucleotide. Synthesis and enzyme studies.

A structural analog of NAD+, NICOTINAMIDE 3,N-4ethenocytosine dinucleotide (epsilonNCD+), has been synthesized, characterized, and compared in activity with the natural coenzyme in several enzyme systems. The Vmax and apparent Km values were determined for NAD+, epsilonNCD+, and epsilonNAD+ (nicotinamide 1, N6-ethenoadenine dinucleotide) with yeast alcohol, horse liver alcohol, pig heart malate, beef liver glutamate, and rabbit muscle lactate and glyceraldehyde-3-phosphate dehydrogenases. The Vmax for epsilonNCD+ was as great or greater than that obtained for NAD+ with three of the enzymes, 60-80 per cent with two others, and 14 percent with one. EpsilonNCD+ was found to be more active than epsilonNAD+ with all six dehydrogenases. EpsilonNCD+ served as a substrate for Neurospora crassa tnadase, but could not be phosphorylated with pigeon liver NAD+ kinase. NAD+ pyrophosphorylase from pig liver was unable to catalyze the formation of epsilonNCD+ from the triphosphate derivative of epsilon-cytidine and nicotinamide mononucleotide, but was able to slowly catalyze the pyrolytic cleavage of epsilonNCD+. The coenzyme activity of epsilonNCD+ with dehydrogenases can be discussed in terms of the close spatial homology of epsilonNCD+ and NAD+, which may allow similar accommodations within the enzyme binding regions.

Animals↗

PubMed1993

Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide.

Two isosteric analogues of nicotinamide adenine dinucleotide, C-NAD (11) and C-PAD (12), in which the nicotinamide riboside portion is replaced by a C-nucleoside, were synthesized from 5-(beta-D-ribofuranosyl)nicotinamide (7) and 6-(beta-D-ribofuranosyl)picolinamide (8), respectively. Nucleoside 7 was prepared from the 2,3-O-isopropylidene-5-O-(tetrahydropyranyl)-D-ribonolactone (13) and 3-cyano-5-lithiopyridine as reported earlier. Nucleoside 8 was obtained by conversion of the bromo function of the 6-(2,3:4,5-di-O-isopropylidene-D-altro-pentitol-1-yl)-2-bromopyrid ine (14) into a carboxamido group followed by mesylation of the anomeric hydroxyl group to give derivative 18. Treatment of 18 with CF3COOH/CHCl3 caused deisopropylidenation with simultaneous cyclization into the desired 6-(beta-D-ribofuranosyl)picolinamide (8). NAD analogues, C-NAD (11) and C-PAD (12), were synthesized by imidazole-catalyzed coupling of the corresponding 5'-monophosphates of 7 and 8 with the adenosine-5'-monophosphate. Dinucleotide 11 was found to inhibit the proliferation of L1210 cells (IC50 = 7 microM) and to be a good competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH, ID50 = 20 microM) as well as bovine glutamate dehydrogenase (GDH, Ki = 15 microM). Interestingly, C-NAD (11) caused extremely potent noncompetitive inhibition of horse liver alcohol dehydrogenase (ADH, Ki = 1.1 nM), whereas C-PAD (12) was found to be a much less potent competitive inhibitor (Ki = 20 microM) of ADH.

Alcohol Dehydrogenase↗

PubMed1969

Nicotinate, quinolinate and nicotinamide as precursors in the biosynthesis of nicotinamide-adenine dinucleotide in barley.

1. The relative efficiencies of nicotinate, quinolinate and nicotinamide as precursors of NAD(+) were measured in the first leaf of barley seedlings. 2. In small amounts, both [(14)C]nicotinate and [(14)C]quinolinate were quickly and efficiently incorporated into NAD(+) and some evidence is presented suggesting that NAD(+) is formed from each via nicotinic acid mononucleotide and deamido-NAD. 3. [(14)C]Nicotinamide served equally well as a precursor of NAD(+) and although significant amounts of [(14)C]NMN were detected, most of the [(14)C]NAD(+) was derived from nicotinate intermediates formed by deamination of [(14)C]nicotinamide. 4. Radioactive NMN was also a product of the metabolism of [(14)C]nicotinate and [(14)C]quinolinate but most probably it arose from the breakdown of [(14)C]NAD(+). 5. In barley leaves where the concentration of NAD(+) is markedly increased by infection with Erysiphe graminis, the pathways of NAD(+) biosynthesis did not appear to be altered after infection. A comparison of the rates of [(14)C]NAD(+) formation in infected and non-infected leaves indicated that the increase in NAD(+) content was not due to an increased rate of synthesis.

Ascomycota↗

PubMed2002

The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside.

Oncolytic C-nucleosides, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) and benzamide riboside (3-beta-D-ribofuranosylbenzamide) are converted in cell into active metabolites thiazole-4-carboxamide- and benzamide adenine dinucleotide, TAD and BAD, respectively. TAD and BAD as NAD analogues were found to bind at the nicotinamide adenine dinucleotide (cofactor NAD) site of inosine monophosphate dehydrogenase (IMPDH), an important target in cancer treatment. The synthesis and evaluation of anticancer activity of a number of C-nucleosides related to tiazofurin and nicotinamide riboside then followed and are reviewed herein. Interestingly, pyridine C-nucleosides (such as C-nicotinamide riboside) are not metabolized into the corresponding NAD analogues in cell. Their conversion by chemical methods is described. As dinucleotides these compounds show inhibition of IMPDH in low micromolar level. Also, the synthesis of BAD in metabolically stable bis(phosphonate) form is discussed indicating the usefulness of such preformed inhibitors in drug development. Among tiazofurin analogues, Franchetti and Grifantini found, that the replacement of the sulfur by oxygen (as in oxazafurin) but not the removal of nitrogen (tiophenfurin) of the thiazole ring resulted in inactive compounds. The anti cancer activity of their synthetic dinucleotide analogues indicate that inactive compounds are not only poorly metabolized in cell but also are weak inhibitors of IMPDH as dinucleotides.

Antineoplastic Agents↗

PubMedDate not supplied

Growth of Mycoplasma synoviae in a medium supplemented with nicotinamide instead of B-nicotinamide adenine dinucleotide.

The cultivation of Mycoplasma synoviae (MS) on growth medium requires supplementation with B-nicotinamide adenine dinucleotide (NAD), an expensive and relatively unstable compound. Strains of MS were adapted (selected) to grow in a medium supplemented instead with nicotinamide, a stable and inexpensive substance that can be heat-sterilized in the medium without impairing its growth-promoting properties. MS plate agglutinating antigens grown in nicotinamide-enriched media were comparable in yield and serological reaction to antigens grown with NAD supplementation.

Antigens, Bacterial↗

PubMedDate not supplied

[The dynamic biosynthesis of nicotinamide coenzymes from nicotinamide and nicotinic acid in rat tissues].

Dynamics of nicotinamide coenzyme biosynthesis in rat tissues has been studied systematically with previous injection of two main precursors nicotinic acid and nicotinamide (50 mg/100 g of weight. This process is characterized by exact tissue specificity. As a precursor of NAD-biosynthesis nicotinamide was used more intensively in the liver and brain tissues. In the mucous tissue of intestine nicotinic acid was utilized more intensively. An increase in the NADP+ content in tissues with high level of NAD+ biosynthesis is limited as a result of competition between these two processes for the intracellular ATP level.

Animals↗

PubMed1998

Interactions of reduced and oxidized nicotinamide mononucleotide with wild-type and alphaD195E mutant proton-pumping nicotinamide nucleotide transhydrogenases from Escherichia coli.

The interaction of reduced nicotinamide mononucleotide (NMNH), constituting one half of NADH, with the wild-type and alphaD195E proton-pumping nicotinamide nucleotide transhydrogenase from Escherichia coli was investigated. Reduction of thio-NADP+ by NMNH was catalysed at approximately 30% of the rate with NADH. Other activities including proton pumping and the cyclic reduction of 3'-acetyl-pyridine-NAD+ by NMNH in the presence of NADP+ were more strongly inhibited. The alphaD195 residue is assumed to interact with the 2'-OH moiety of the adenosine-5'-phosphate, i.e., the second nucleotide of NADH. Mutation of this residue to alphaD195E resulted in a 90% decrease in activity with NMNH as well as NADH as substrate, suggesting that it produced global structural changes of the NAD(H) binding site. The results suggest that the NMN moiety of NADH is a substrate of transhydrogenase, and that the adenine nucleotide is not required for catalysis or proton pumping.

Amino Acid Sequence↗

PubMed1982

The distribution of enzymes which synthesize nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate in monkey, rabbit, and ground squirrel retinas.

The activity of adenosinetriphosphate:nicotinamide adenylyltransferase (EC 2.7.7.1) was measured in all the layers of monkey, rabbit, and ground squirrel retinas. Nicotinamide adenine dinucleotide (NAD) kinase (EC 2.7.1.23) distribution was measured in monkey and rabbit retinas. An attempt was made to measure NAD synthetase (EC 6.3.5.1), but the activities in the retinal layers were too low to produce a reliable increment in the levels of endogenous NAD. In monkey retina the adenylyl transferase was highest by far in the outer and inner nuclear layers, lower and variable in ganglion cell and fiber layers, and almost absent elsewhere. Rabbit retina differed in that activity was nearly absent in the outer nuclear layer, whereas in the ground squirrel outer nuclear layer activity was double that of the inner nuclear layer. The species differences suggest that adenylyl transferase is almost absent from cone cell nuclei and high in rod cell nuclei. NAD kinase distribution in monkey retina was almost the mirror image of that of adenylyl transferase.

Animals↗

PubMed1993

Thermodynamics of reactions of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate.

The thermodynamics of six reactions of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate is discussed both from the viewpoint of the chemical equations and the biochemical equations for these reactions. Tables of the standard enthalpies of formation and standard Gibbs energies of formation of species are presented and are used to calculate standard enthalpies of reaction, standard Gibbs energies of reaction, and equilibrium constants K of chemical reactions at 25 degrees C, 1 bar, and ionic strengths of 0, 0.1, and 0.25 M. These tables are used to calculate standard transformed enthalpies of formation and standard transformed Gibbs energies of formation of reactants, standard transformed enthalpies of reaction, standard transformed Gibbs energies of reaction, and apparent equilibrium constants K' of biochemical reactions at 25 degrees C, 1 bar, pH 7, and ionic strengths of 0, 0.1, and 0.25 M. Since these reactions do not involve pK's of acid groups in the vicinity of pH 7, these reactions produce exactly 0, 1, or 2 mol of H+ per mole of reaction. The calculations are compared with experimental values.

Alanine Dehydrogenase↗

PubMed2005

Development of a simple and efficient method for assaying cytidine monophosphate sialic acid synthetase activity using an enzymatic reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide converting system.

A new reliable method to assay the activity of cytidine monophosphate sialic acid (CMP-Sia) synthetase (CSS) has been developed. The activation of sialic acids (Sia) to CMP-Sia is a prerequisite for the de novo synthesis of sialoglycoconjugates. In vertebrates, CSS has been cloned from human, mouse, and rainbow trout, and the crystal structure has been resolved for the mouse enzyme. The mouse and rainbow trout enzyme have been compared with respect to substrate specificity, demonstrating that the mouse enzyme exhibits a pronounced specificity for N-acetylneuraminic acid (Neu5Ac), while the rainbow trout CSS is equally active with either of three Sia species, Neu5Ac, N-glycolylneuraminic acid (Neu5Gc), and deaminoneuraminic acid (KDN). However, molecular details that explain the pronounced substrate specificities are unknown. Understanding the catalytic mechanisms of these enzymes is of major importance, since CSSs play crucial roles in cellular sialylation patterns and thus are potential drug targets in a number of pathophysiological situations. The availability of the cDNAs and the obtained structural data enable rational approaches; however, these efforts are limited by the lack of a reliable high-throughput assay system. Here we describe a new assay system that allows product quantification in a reduced nicotinamide adenine dinucleotide (NADH)-dependent color reaction. The activation reaction catalyzed by CSS, CTP+Sia-->CMP-Sia+pyrophosphate, was evaluated by a consumption of Sia, which corresponds to that of NADH on the following two successive reactions: (i) Sia-->pyruvate+ManNAc (or Man), catalyzed by a sialic acid lyase (SAL), and (ii) pyruvate+NADH-->lactate+oxidized nicotinamide adenine dinucleotide (NAD+), catalyzed by a lactate dehydrogenase (LDH). Consumption of NADH can be photometrically monitored on a microtiter plate reader for a number of test samples at the same time. Furthermore, based on the quantification of CSS used in the SAL/LDH assay, relative activities toward Sia derivatives have been obtained. The preference of mouse CSS toward Neu5Ac and the ability of the rainbow trout enzyme to activate both KDN and Neu5Ac were confirmed. Thus, this simple and time-saving method is suitable for a systematic comparison of enzyme activity of structurally mutated enzymes based on the relative specific activity.

Animals↗

PubMed1997

Nicotinamide derivatives as a new class of gastric H+/K(+)-ATPase inhibitors. 1. Synthesis and structure-activity relationships of N-substituted 2-(benzhydryl- and benzylsulfinyl)nicotinamides.

A new series of N-Substituted 2-(benzhydryl- and benzylsulfinyl)nicotinamides 7 and 8 were synthesized. Upon acid activation in the acidic environment of the parietal cell, these compounds are converted into their active forms, 2,3-dihydro-3-oxoisothiazolo[5,4-b]pyridines 5, which inhibit gastric H+/K(+)-ATPase. Inhibitory activities against [14C]aminopyrine accumulation stimulated by dibutyryl cAMP in isolated rabbit parietal cells in vitro and histamine-induced gastric acid secretion in pylorus-ligated rats by intraduodenal administration in vivo were evaluated, and the structure-activity relationships were examined. Among the compounds synthesized, 2-[(2,4-dimethoxybenzyl)sulfinyl]-N-(4-pyridyl)nicotinamide (8b) showed potent inhibitory activities in vitro and in vivo equivalent to those of omeprazole, a typical H+/K(+)-ATPase inhibitor. Moreover, 8b was much more stable at neutral and weakly acidic pH than omeprazole, lansoprazole, and pantoprazole. Compound 8b is considered to be a promising agent for treating acid-related gastrointestinal disorders.

Aminopyrine↗

PubMed1977

X-ray structures of two oxidation states of a flavin-nicotinamide biscoenzyme and models for flavin--nicotinamide interactions.

The flavin nicotinamide biscoenzymes Flox(-)--C3--Nic+ and H2Flred--C3--Nic+ assume extended conformations in the solid state. In both derivatives the nicotinamide and flavin groups associate through hydrogen bonding. The bending angle of the reduced flavin moiety is less than half that in any previously reported 1,5-dihydroflavin structure. This effect is apparently due to ring stacking interactions.

Chemical Phenomena↗

PubMed1965

The activities of nicotinamide mononucleotide adenylyltransferase and of nicotinamide-adenine dinucleotide kinase in the livers of rats subjected to different hormonal treatments.

1. The activities of NMN adenylyltransferase and of NAD(+) kinase have been measured in the livers of adrenalectomized or alloxan-diabetic rats and in the livers of rats treated with glucagon, pituitary growth hormone or thyroxine. 2. The activities of these enzymes have been compared with the effects of the same treatments on the nicotinamide nucleotide concentrations in the liver. 3. Alloxandiabetes (+37%) and thyroxine (+27%) both increased the activity of NMN adenylyltransferase. The other treatments were without effect on this enzyme. 4. Only thyroxine increased the activity of NAD(+) kinase significantly (+26%) although both adrenalectomy and glucagon tended to increase its activity. 5. The activity of NAD(+) glycohydrolase was measured in the livers of diabetic rats, and in the livers of rats treated with either growth hormone or thyroxine. Of these treatments, only growth hormone altered the enzyme activity (+26%, calculated on a total hepatic activity basis). 6. Female rats had a greater hepatic NAD(+)-kinase activity than males but there was no sex difference with respect to NMN adenylyltransferase. 7. The lack of correlation between the maximum potential activity of these three enzymes and the known changes of the nicotinamide nucleotides in each of the hormone conditions is discussed.

Adenine Nucleotides↗

PubMed1979

Relationship between the ability of nicotinamide to maintain nicotinamide-adenine dinucleotide in rat liver cell culture and its effect on cytochrome P-450.

Rat hepatocytes cultured for 24 h lose 60% of their NAD content. Treatment with nicotinamide prevents the loss of NAD as well as the previously reported loss of cytochrome P-450, suggesting a possible causal relationship. However, isonicotinamide also prevents the loss of cytochrome P-450, but does not increase the concentration of NAD, demonstrating that the ability of nicotinamide to maintain cytochrome P-450 is not apparently related to its effect on the NAD content of cultured hepatocytes.

Animals↗

PubMed1989

Stimulation of endogenous L-dopa biosynthesis--a new principle for the therapy of Parkinson's disease. The clinical effect of nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotidephosphate (NADPH).

The coenzyme nicotinamide adenine dinucleotide (NADH) has been used as a novel medication in 161 Parkinson patients in an open label trial. In all but 18 patients (11.2%) an improvement in their disability was observed. 115 patients (71.4%) showed a very good (better than 30%) response, and 28 patients (17.4%) a moderate response up to 30%. The best results were obtained with a dose of 25 to 50 mg every second day by i.v. administration. Concomitantly with the improvement in disability, the urine HVA level increased significantly, indicating a stimulation of endogenous L-DOPA biosynthesis. 8 patients have been treated with nicotinamide adenine dinucleotidephosphate (NADPH), 5 of whom exhibited an improvement in their disability from 35 to 55%. The other 3 showed a moderate response of 20 to 25%. In all these patients an increase in the urine level of HVA was detected, reflecting elevated endogenous L-DOPA production.

Adult↗