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At least 19 recordsLinked to original sources
PubMed1975

Renal excretion of N'1-methylnicotinamide in the rat.

The renal excretion of N'1-methylnicotinamide (NMN) was studied in the rat. Renal clearance experiments clearly demonstrated that: 1) NMN is secreted; 2)a tubularmaximum (Tm), 7 mumol/min per kg, could be reached; and 3)NMN secretion is inhibitedby a competitive inhibitor, mepiperphenidol. In free-flow micropuncture experiments, animals were infused with plasma concentrations of NMN ABOVE Tm; the TF/P NMNto TF/P inblin ratio for proximal and distal samples was 2.34 and 2.28, respectively, indicating that NMN is secreted in the proximal tubules and is not secreted orreabsorbed in the distal tubules. This finding was further confirmed by intratubularmicroinjections of ['14C]NMN into rats. In diuretic animals approxiamately 10%of the NMN injected into early proximal tubules was reabsorbed, but no reabsorption could be detected after distal injections. The nondiuretic animals showed no significant reabsorption of NMN. It was concluded that NMN transport is a carrier-mediated process and that reabsorption, if it occurs, plays only a minor role.

Absorption↗
PubMed1979

Isolation and properties of a glycohydrolase specific for nicotinamide mononucleotide from Azotobacter vinelandii.

A glycohydrolase that catalyzes the irreversible conversion of NMN to nicotinamide and ribose 5-phosphate has been partially purified from a sonic extract of Azotobacter vinelandii. The enzyme is highly specific for NMN. NAD, NADP, nicotinic acid-adenine dinucleotide, nicotinamide riboside and alpha-NMN are not significantly hydrolyzed by this enzyme, nor do they compete with NMN. The enzyme also exhibits an absolute dependence on guanylic acid derivatives with following order of relative effectiveness: GTP, guanosine 5'-tetraphosphate greater than dGTP, GDP, 2'-GMP, 3'-GMP greater than GMP, dGMP. A heat-resistant, nondialyzable factor which could replace the GTP requirement was found in the sonic extract. The Ka for GTP and the Km for NMN in the presence of GTP at 1mm were calculated to be 0.025 mM and 4.5 mM respectively. GMP, dGMP, and dCMP were found to be effective inhibitors of the enzyme when 1 mM GTP was also present. The kinetic data suggest that the binding site for these mononucleotides is distinct from the active site or the GTP binding site. The ability of this enzyme to cleave NMN is suggestive of a metabolic role of the enzyme in selective conversion of NMN to nicotinamide, which, in turn, would be re-utilized by the cell as a precursor of NAD via nicotinic acid.

Azotobacter↗
PubMed1977

Automated and manual determination of N1-methylnicotinamide in urine.

An automated AutoAnalyzer method and a manual adaptation of the automated method are described for determining N1-methylnicotinamide (NMN) in urine. The new methods incorporate improvements presented by Pelletier and Campbell (Anal. Biochem. 3:60, 1962) for the fluorometric determination of NMN after condensation with methyl ethyl ketone (MEK). The new methods are simpler and not limited by the usage of a single brand of MEK. Various brands of MEK into which hydrogen peroxide had been added in order to catalyze the formation of the condensation product were used and found to give comparable NMN values with different urine specimens. Results of the analysis of 21 urine specimens by the new procedures agreed well with those by the method of Carpenter and Kodicek (Biochem. J. 46: 421, 1950) for which interpretation guidelines exist. Furthermore, it was found that eluates from the chromatographic purification of thiamine in urine with Decalso retained the NMN present in the original specimens, gave complete recoveries of added NMN and were free from nearly all interfering fluorescing substances; this purification would be advantageous for determining with accuracy and precision NMN levels in the urine of deficient subjects and could be used routinely when thiamine analysis has to be performed.

Autoanalysis↗
PubMed1976

Transport of organic cations and anions by choroid plexus.

The accumulation of organic cations and anions by the isolated rabbit choroid plexus was measured and the results were considered in comparison to in vivo measurements of transport using the ventriculocisternal perfusion technique also in rabbits. The accumulation in vitro of 3H-p-aminohippurate (PAH) and 14C-N1-methylnicotinamide (NMN) was shown to be organic anion and cation specific and dependent upon oxidative metabolism since tissue/medium ratios were reduced by competitive inhibitors including dibenamine and mepiperphenidol for cation transport and probenecid for anion transport and were also reduced by cyanide and dinitrophenol. Rabbits pretreated with chlorpromazine and anesthetized with pentobarbital were perfused lateral ventricle to cisterna magna with artificial cerebrospinal fluid containing inulin, 3H-PAH and 14C-NMN. Ratios of concentrations of these substances in the perfusate to those infused were calculated. Significant reductions in the ratios for PAH and NMN compared to unulin were obtained when low rates of perfusion, 40mul/min, were employed with low concentrations of PAH (2 mug/ml) and NMN (0.2 mug/ml). Probenecid (10(-3)M) specifically increased the ratio for PAH without affecting the NMN ratios. Mepiperhenidol (10(-o) M) blocked NMN transport but no PAH. The data and calculated clearances indicate that these prototype anions and cations may be actively transported out of cerebrospinal fluid, but for cations only at a low rate.

Aminohippuric Acids↗
PubMed1979

uvrC gene function in excision repair in toluene-treated Escherichia coli.

We have examined the role of the uvrC gene in UV excision repair by studying incision, excision, repair synthesis, and DNA strand reformation in Escherichia coli mutants made permeable to nucleoside triphosphates by toluene treatment. After irradiation, incisions occur normally in uvrC cells in the presence of nicotinamide mononucleotide (NMN), a ligase-blocking agent, but cannot be detected otherwise. We conclude that repair incisions are followed by a ligation event in uvrC mutants, masking incision. However, a uvrC polA12 mutant accumulates incisions only slightly less efficiently than a polA12 strain without NMN. Excision of pyrimidine dimers is defective in uvrC mutants (polA(+) or polA12) irrespective of the presence or absence of NMN. DNA polymerase I-dependent, NMN-stimulated repair synthesis, which is demonstrable in wild-type cells, is absent in uvrC polA(+) cells, but the uvrC polA12 mutant exhibits a UV-specific, ATP-dependent repair synthesis like parental polA12 strains. A DNA polymerase I-mediated reformation of high-molecular-weight DNA takes place efficiently in uvrC polA(+) mutants after incision accumulation, and the uvrC polA12 mutant shows more reformation than the polA12 strain after incision. These results indicate that normal incision occurs in uvrC mutants, but there appears to be a defect in the excision of pyrimidine dimers, allowing resealing via ligation at the site of the incision. The lack of NMN-stimulated repair synthesis in uvrC polA(+) cells indicates that incision is not the only requirement for repair synthesis.

DNA Polymerase I↗
PubMed1978

DNA polymerase I-mediated ultraviolet repair synthesis in toluene-treated Escherichia coli.

DNA synthesis after ultraviolet irradiation is low in wild type toluene-treated cells. The level of repair incorporation is greater in strains deficient in DNA polymerase I. The low level of repair synthesis is attributable to the concerted action of DNA polymerase I and polynucleotide ligase. Repair synthesis is stimulated by blocking ligase activity with the addition of nicotinamide mononucleotide (NMN) or the use of a ligase temperature-sensitive mutant. NMN stimulation is specific for DNA polymerase I-mediated repair synthesis, as it is absent in isogenic strains deficient in the polymerase function or the 5' leads to 3' exonuclease function associated with DNA polymerase I. DNA synthesis that is stimulated by NMN is proportional to the ultraviolet exposure at low doses, nonconservative in nature, and is dependent on the uvrA gene product but is independent of the recA gene product. These criteria place this synthesis in the excision repair pathway. The NMN-stimulated repair synthesis requires ATP and is N-ethylmaleimide-resistant. The use of NMN provides a direct means for evaluating the involvement of DNA polymerase I in excision repair.

DNA Polymerase I↗
PubMed1975

Binding of N1-methylnicotinamide and p-aminohippuric acid to a particulate fraction from dog kidney.

The active secretion of organic ions by the kidney may be described by the following models: 1)binding to a carrier protein and 2) a translocation process across the membrane. The feasibility of such a model was tested by measuring binding of either an organic cation, N1-methylnicotinamide (NMN) or an organic anion p-aminohippuric acid (PAH) to particulate material obtained from dog renal cortex tissue. The method employed was one in which the bound and free forms of the ligand were separated by centrifugation through a gel matrix. Binding of NMN and PAH was found to be tissue specific. In addition, binding was pH, time, temperature, protein-concentration and ligand-concentration dependent. Saturation of binding for either ligand was observed at concentrations greater than 50 mM, suggesting low affinity. Interestingly, a positive cooperative effect was observed for binding of either NMN or PAH to the particulate material. Although binding was associated only with particulate material, the binding proteins were released from the membrane system(s) by treatment with the nonionic detergent Lubrol WX. These studies show that NMN and PAH binding share many features in common but that the two processes are independent of each other. The results are consistent with, but do not prove, the model.

Aminohippuric Acids↗
PubMed2026

Fetal hypoxia causes oocyte oxidative stress damage via the Sirt3/Sod2 pathway and can be alleviated by nicotinamide mononucleotide.

Environmental hypoxia exerts detrimental effects on the reproductive capabilities of both humans and animals. A fetal hypoxia model was established in which fetal mice were kept in a high-plateau hypoxic setting from embryonic day (E) 0 to 16.5. In our previous research, we found that fetal hypoxia exposure perturbs the methylation of imprinted genes in adult sperm and causes intergenerational placental impairments in male offspring. However, the specific impacts of fetal hypoxia on the female reproductive system, particularly regarding oocyte maturation, remain poorly understood. First, we found that fetal hypoxia mice exhibited a significant reduction in the average number of pups per litter. We conducted a comprehensive analysis of the transcriptome in oocytes from the hypoxic group and investigated the metabolic alterations within the follicular microenvironment. Fetal hypoxic stress contributed to cleavage and blastocyst rate reduction and induced early apoptosis and DNA damage triggered by mitochondrial dysfunction, oxidative stress aggravation and Sirt3/Sod2 downregulation. Additionally, administration of nicotinamide mononucleotide (NMN) has been shown to prevent oocytes from mitochondrial dysfunction and developmental impairment by increasing the expression of Sirt3/Sod2 and autophagy. The number of pups per litter in fetal hypoxia mice was reduced by 57.7% compared to the control group, while NMN intervention could restore it to 73.1% of the control group. These results indicate that fetal hypoxia exposure exerts multiple potential damages to adult female reproduction, while highlighting the clinical potential of NMN supplementation as a targeted intervention to alleviate such hypoxia-associated female reproductive impairment.

Animals↗
PubMed1977

Secretion of monoquaternary ammonium compounds by guinea pig small intestine in vivo.

In anesthetized guinea pigs N-(3H)methylscopolamine (NMScop), N1-(14C)methylnicotinamide (NMN), and (14C)tetraethylammonium (TEA), administered intravenously, were secreted against a concentration gradient into the lumen of the small intestine. The concentration ratio of unmetabolized ammonium base in the intestinal lumen to that in the plasma was 4.3 and 6.5 for NMScop and NMN, respectively, 75 min after the intravenous injection of 1 nmole/g body weight of the individual compounds. The corresponding value for TEA after 180 min was 2.0. The establishment of the concentration gradient between intestinal lumen and plasma was diminished with increasing doses. An excess of NMN inhibited the uphill transport of NMScop. Since the electrical potential difference across the intestinal epithelium and a 'fluid circuit' mechanism cannot solely account for the observed accumulation of the monoquaternary ammonium compounds in the intestinal lumen, the evidence presented supports previous in vitro findings that the small intestine is capable of actively secreting organic cations.

Animals↗
PubMed1979

The biosynthesis of nicotinamide adenine dinucleotide during early stages of frog embryonic development of haploid and diploid embryos.

1. Concentration of NAD during embryonic development of haploid and diploid embryos of frog was followed. NAD content in haploid embryonic forms is twice that in diploid embryos. 2. The variation of the NMN adenylyltransferase activity in the oocytes and during the first states of embryonic development as surveyed in the nuclear soluble fraction and the nuclear insoluble fraction (chromatin). 3. The enzyme activity in the soluble fraction is low during embryonic development and shows higher values in haploid embryos. 4. In the nonfertilized mature oocytes, the NMN adenylyltransferase activity is sixfold higher in the insoluble chromatin fraction than in the soluble fraction. 5. The evolution of the NMN adenylyltransferase in the insoluble chromatin fraction also shows higher values in haploid embryos, as compared with diploid forms.

Animals↗
PubMed1976

An investigation of the nicotinamide-adenine dinucleotide-induced 'tightening' of the structure of glyceraldehyde 3-phosphate dehydrogenase.

An investigation was made of the effect of NAD+ analogues on subunit interactions in yeast and rabbit muscle glyceraldehyde 3-phosphate dehydrogenases by using the subunit exchange (hybridization) method described previously [e.g. see Osborne & Hollaway (1975) Biochem. J. 151, 37-45]. The ligands ATP, ITP, ADP, AMP, cyclic AMP and ADP-ribose like NADH, all caused an apparent weakening of intramolecular subunit interactions, whereas NAD+ caused an apparent increase in the stability of the tetrameric enzyme molecules. A mixture of NMN and AMP, although it did not simulate completely the NAD+-induced 'tightening' of the enzyme structure, did result in a more than 20-fold decrease in the rate of subunit exchange compared with that in the presence of AMP alone. These results show that occupancy of the NMN subsite of the enzyme NAD+-binding site is insufficient in itself to give the marked tightening of the enzyme structure induced by NAD+. The 'tightening' effect is specific in that it seems to require a phosphodiester link between NMN and ADP-ribose. These effects are discussed in terms of the detailed X-ray structure of the lobster holoenzyme [Buehner et al. (1974) J. Mol. Biol. 90, 25-49].

Adenosine Diphosphate↗
PubMed2025

A Sequence Motif Enables Widespread Use of Non-Canonical Redox Cofactors in Natural Enzymes.

Non-canonical redox cofactors (NRCs) are promising alternatives to nicotinamide adenine dinucleotide (phosphate) (NAD(P)+) for biomanufacturing due to low cost and exquisite electron delivery control, yet their adoption is limited by the scarcity of compatible enzymes. Here, we screened the aldehyde dehydrogenase (ALDH) protein family and identified a conserved RH/QxxR sequence motif that enables widespread NRC activity among natural enzymes. Bos taurus ALDH3a1 and Pseudanabaena biceps ALDH exhibit unprecedented turnover with nicotinamide mononucleotide (NMN+), with kcat values matching or exceeding that of NAD+ and surpassing most engineered NRC-active enzymes by 10 to 105-fold, based on the relative NRC to native activity. Structural and dynamic analyses reveal this motif reinforces cofactor positioning and pre-organizes the active site without dependence on the adenosine monophosphate moiety of NAD+. When introduced into diverse ALDH scaffolds, the RH/QxxR motif enhances NMN+ activity up to 60-fold. In addition to NMN+, this motif also supports activity across multiple non-nucleotide, simple synthetic NRCs such as 1-(2-carbamoylmethyl)nicotinamide (AmNA+). These findings elucidate Nature's solution to the engineering challenge of obtaining NRC-active enzymes and offers a blueprint to mine latent evolutionary plasticity in natural enzymes that serve as superior engineering starting points.

Active site pre-organization↗
PubMed1975

Nicotinamide adenine dinucleotide phosphate-specific glutamate dehydrogenase of Neurospora. III. Inactivation by nitration of a tyrosine residue involved in coenzyme binding.

Neurospora glutamate dehydrogenase (NADP-specific) is rapidly inactivated upon reaction with tetranitromethane. This inactivation is completely prevented by the presence of coenzyme (NADP) or nicotinamide mononucleotide (NMN) but not by substrate. NADH, or 2'-monophosphoadenosine-5'-diphosphoribose. Amino acid analysis indicates that the primary effect of modification is nitration of a single residue of tyrosine per polypeptide chain. We have identified the reactive tyrosine by isolation of a single, uniquely labeled peptide after hydrolysis with trypsin followed by cleavage with cyanogen bromide. The modified residue proved to be tyrosine-168 in the linear sequence. This residue is not present in the part of the sequence that had been previously implicated as involved in the binding of the adenylate portion of the coenzyme. Both NMN and 2-monophosphoadenosine-5'-diphosphoribose act as competitive inhibitors of NADP in the oxidation of glutamate with Ki values of 4.65 x 10(-4) M and 4.30 x 10(-4) M, respectively. Thus, the specific protection afforded by NADP and NMN, but not by 2'-monophosphoadenosine-5'-diphosphoribose, indicates that tyrosine-168 is involved in binding the nicotinamide portion of the coenzyme.

Amino Acid Sequence↗
PubMed1976

Effect of substrate pretreatment on renal organic ion transport in the adult rat.

The ability of renal cortical slices to accumulate PAH and NMN was not significantly affected by pretreatment of adult rats with large doses of PAH. Pretreatment of adult rats with THAM significantly increased PAH accumulation but had no effect on NMN. Inulin and PAH clearance and filtration fraction were significantly decreased by PAH pretreatment but unaffected by THAM pretreatment. The effects of pretreatment on transport are probably due to non-specific toxicity.

Aminohippuric Acids↗
PubMed1978

The influence of pH on the sex-related differences in renal organic ion transport.

The stimulating effects of elevated medium pH and androgen on in vitro transport of p-aminohippurate and N-methylnicotinamide (NMN) were additive, although the androgenic effect was pH-dependent only in the case of NMN. The similarity of response of the 2 systems supports the idea of a common passive efflux pathway for organic anions and cations.

Aminohippuric Acids↗
PubMed1975

Depression by NAD of x-ray-induced repair-type DNA synthesis in toluene-treated Bacillus subtilis.

NAD prevents a DNA repair-type synthesis that is dependent on polymerase I in toluene-treated, X-irradiated Bacillus subtilis. In unirradiated preparations, NAD had little effect on an ATP-dependent, semiconservative synthesis but partially inhibited a repair-type synthesis. In a mutant lacking polymerase I (polA1-), the presence of NAD did not affect dTTP utilization in DNA synthesis. Nicotinamide mononucleotide (NMN) partially reverses the NAD inhibition of repair-type DNA synthesis. NADP and FAD were ineffective as substitutes for NAD. Since NAD is the cofactor for polynucleotide ligase in Bacillus subtilis and NMN is known to discharge AMP from the active AMP ligase complex, it is proposed that activation of DNA ligase reduces dTMP incorporation by reducing sites for, or limiting DNA polymerase I action.

Adenosine Triphosphate↗
PubMed1976

The interaction of borate and sulfite with pyridine nucleotides.

The kinetics and equilibria of the borate interaction at ribose with NAD+ and NMN+ have been measured using as a chromophoric probe the perturbation effect borate has on the addition of sulfite to the 4 position of the nicotinamide ring. NAD+ and NMN+ have more favorable borate association constants than do their corresponding sulfite addition complexes. The rate of interaction of the ribose moiety with borate at low borate buffer concentration is dependent on the concentration of both borate and boric acid. At high borate concentration the rate becomes independent of borate concentration, indicating the existence of a two-step process for the interaction of NAD-sulfite with borate with a change of rate-determining step from the interaction of the ribose hydroxyl group with borate at low borate to an elimination of sulfite at high borate concentration. A linear free energy relationship with a slope of 0.94 describes an increased reactivity of the nucleotide for sulfite as the affinity of the nucleotide for sulfite increases.

Binding Sites↗
PubMed1976

Effects of substrate and inhibitor binding on thermal and proteolytic inactivation of rat liver transhydrogenase.

The thermostability and proteolytic inactivation of rat liver submitochondrial particle transhydrogenase was studied in the presence of pyridine dinucleotide substrates and a variety of divalent metal and nucleotide inhibitors. Relative to the unliganded enzyme, the NADPH-enzyme complex was more thermostable and showed a twofold greater rate of tryptic inactivation, while the NADP+-enzyme complex was more thermolabile and only slightly more susceptible to tryptic inactivation. Neither NAD+ nor NADH significantly affected thermostability or proteolysis. Similar effects of these ligands were observed for the non-energy-linked and energy-linked transhydrogenase reactions, indicating that both activities are catalyzed by the same enzyme. In thermal experiments, acetyl-CoA, 2'-AMP, and NMNH stabilized, palmitoyl-CoAlabilized, and dephospho-CoA, CoA, NMN+, and 5'-AMP had little effect on enzyme stability. Tryptic inactivation was inhibited by 2'-AMP and NMN+ but was not influenced by the other nucleotide inhibitors. Divalent metal ion inhibitors (Mg2+, Ca2+, Mn2+, Ba2+, and Sr2+) stabilized transhydrogenase against thermal inactivation and promoted tryptic inactivation.

Animals↗