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Query: UNIPROT:P06889 (Mol)
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The pyridine nucleotides have important non-redox activities as cellular effectors and metabolic regulators [1-3]. The enzyme-catalyzed cleavage of the nicotinamide-ribosyl bond of NAD+ and the attendant delivery of the ADPRibosyl moiety to acceptors is central to these many diverse biological activities. Included are the medically important NAD-dependent toxins associated with cholera, diphtheria, pertussis, and related diseases [4]; the reversible ADPRibosylation-mediated biological regulatory systems [5,6]; the synthesis of poly(ADPRibose) in response to DNA damage or cellular division [7]; and the synthesis of cyclic ADPRibose as part of an independent, calcium-mediated regulatory system [8]. As will be presented in this chapter, all evidence points to both the chemical and enzyme-catalyzed cleavage of the nicotinamide-ribosyl bond being dissociative in character via an oxocarbenium intermediate.
Mol Cell Biochem 1994 Sep
PMID:NAD hydrolysis: chemical and enzymatic mechanisms. 789 70

Nicotinamide (NIC) is known to increase the synthesis of pyridine nucleotides and also to inhibit the hydrolysis of them to ADP-ribose, which in turn is involved in Ca2+ release from mitochondria via the ADP ribosylation of crucial mitochondrial proteins. In this work, we test the potential ability of NIC to be a late protective agent against CCl4-induced liver necrosis. We observed that 1 g/kg po NIC, 30 min before or 6 or 10 hr after CCl4 (1 ml/kg), given ip as a 20% (v/v) solution in olive oil, was able to significantly prevent the necrogenic effect of the hepatotoxin at 24 hr as evidenced by determination of isocitric dehydrogenase activity in plasma or by histological observation. NIC administration 6 hr after CCl4 prevented fatty liver induced by hepatotoxin at 24 hr. NIC did not modify CCl4-induced lipid peroxidation process at 1 hr after CCl4 and decreased the covalent binding of 14CCl4 to lipids. NIC decreased the levels of 14CCl4 reaching the liver when given 30 min before hepatotoxin but not when given 6 hr after it. NIC lowered body temperature of rats at 1, 3, and 6 hr and augmented it at 24 hr after CCl4. NIC concentrations in liver as determined by GC/MS/SIM analysis were 21 micrograms/g liver 1 hr after administration and 53 micrograms/g at 3 hr. Late preventive effects of NIC against CCl4 induced liver necrosis when given at 6 or 10 hr after CCl4 are compatible with the hypothesis that NIC restores mitochondrial ability for Ca2+ uptake. This hypothesis remains to be proved and is being further challenged in our laboratory.
Exp Mol Pathol 1994 Jun
PMID:Nicotinamide late protective effects against carbon tetrachloride-induced liver necrosis. 795 79

The mechanisms by which interleukin-1 (IL-1) exerts destructive action on the pancreatic islet beta-cells remain elusive. Fragmentation of DNA leading to the activation of poly(ADP-ribose) synthetase was investigated in the present study, by assessing the nuclear response to cytokines in rat pancreatic islets. Nuclear fractions display Mg(2+)-dependent poly(ADP-ribose) synthetase activity catalyzing the incorporation of [adenine-U-14C]NAD, with Ka and Km for Mg2+ and NAD amounting to 0.86 mM and 0.43 mM, respectively. Exposure of the nuclear fraction to rIL-1 beta (10 IU/ml) provoked DNA strand breaks and increased nuclear poly(ADP-ribose) synthetase activity (148.4%, P < 0.01). In intact islets, this nuclear response was observed after 18 h culture in medium containing rIL-1 beta, with a concomitant decrease in NAD (88.5%). Brief periods of pre-incubation (90 min) with rIL-1 beta were unable to induce any nuclear activity. Under these conditions, the presence of IFN-alpha (24 U/ml) and TNF (120 U/ml) was necessary to induce a response to rIL-1 beta. Under the latter experimental conditions, a decrease in NAD content was also observed. The nuclear effects of IL-1 beta were modified by nicotinamide (10 mM), an inhibitor of poly(ADP-ribose) synthetase. It is thus conceivable that an increase in poly(ADP-ribose) synthetase activity together with DNA break is implicated in the beta cytotoxic effect of interleukin-1 beta.
Mol Cell Endocrinol 1994 Jul
PMID:Nuclear response of pancreatic islets to interleukin-1 beta. 795 97

Xanthine dehydrogenase (XDH) is an important precursor to the oxygen radical producing enzyme xanthine oxidase (XO). We found that the apparent activity of rabbit myocardial XDH increased from 2 +/- 1 to 50 +/- 3 microU/g (P < 0.05) following extraction of tissue homogenate with butanol. Further studies suggested that the basis for this observation was a high molecular weight compound which consumes the XDH cofactor, NAD+. Addition of myocardial homogenate to exogenous NAD+ resulted in depletion of NAD+ and concomitant formation of an additional compound (peak A). Both NAD+ consumption and peak A formation were abrogated by prior extraction of homogenate with butanol. Separation of myocardial homogenate by Sephadex chromatography revealed a high molecular weight compound which suppressed activity of purified milk XDH but not xanthine oxidase (XO). This activity co-eluted with the ability of myocardial homogenate to consume added NAD+ and form peak A. The NAD(+)-consuming activity was heat and acid-labile. In addition, nicotinamide was both a product and an inhibitor of the NADase activity, consistent with the existence of a previously described myocardial glycohydrolase. Extraction of tissue with butanol may be necessary to detect low levels of XDH activity in vitro.
J Mol Cell Cardiol 1994 Feb
PMID:Suppression of rabbit myocardial xanthine dehydrogenase activity by an endogenous compound. 800 74

In most vertebrate mitochondrial genomes, the site for initiation of light-strand replication, OL, is found within a cluster of five transfer RNA (tRNA) genes (tRNA(Trp), tRNA(Ala), tRNA(Asn), tRNA(Cys), and tRNA(Tyr)). This region and part of the adjacent cytochrome c oxydase subunit I (COI) gene were sequenced for two crocodilian, two turtle, and one snake species and for Sphenodon punctatus; part of the adjacent nicotinamide adenine dinucleotide dehydrogenase subunit 2 (ND2) gene was also sequenced for the crocodilian and turtle species. All had the typical vertebrate gene order. The turtles and the snake have a lengthy noncoding sequence between the tRNA(Asn) and tRNA(Cys) genes that we assumed to be homologous to the mammalian OL. The crocodilians and Sphenodon lack such a sequence, a condition they share with birds. Most proposed phylogenies for the amniotes require that OL at this position was lost at least twice during their diversification or was evolved independently more than once. Within the five tRNA genes, frequencies of substitutions are much higher in loops than in stems. Many loops vary dramatically in size among the species; in the most extreme case, the D-arm of the Sphenodon tRNA(Cys) is a "D-arm replacement" loop of seven nucleotides. Frequency of transitions in stems is relatively uniform across tRNAs, but frequency of transversions varies greatly. Mismatches in stems are infrequent, and their relative frequency in a specific tRNA is unrelated to the frequency of substitution in the corresponding gene. Several features of mammalian mitochondrial tRNAs are conserved in WANCY tRNAs throughout amniotes. The inferred initiation codon for COI is GTG in crocodilians, turtles, and the snake, a condition they share with fishes, certain amphibians, and birds. TTG appears to be the initiation codon for COI in Sphenodon; if correct, this would be a novel initiation codon for vertebrate mitochondrial DNA. Phylogenetic analyses of the inferred amino acid sequences of ND2 and COI support the sister-group relationship of birds and crocodilians and suggest that mammals are an early derived lineage within the amniotes.
Mol Biol Evol 1994 May
PMID:Evolution of the WANCY region in amniote mitochondrial DNA. 801 29

Three-dimensional crystal structures of holo (ternary complex enzyme-NAD-azide) and apo NAD-dependent dimeric formate dehydrogenase (FDH) from the methylotrophic bacterium Pseudomonas sp. 101 have been refined to R factors of 11.7% and 14.8% at 2.05 and 1.80 A resolution, respectively. The estimated root-mean-square error in atomic co-ordinates is 0.11 A for holo and 0.18 A for apo. X-ray data were collected from single crystals using an imaging plate scanner and synchrotron radiation. In both crystal forms there is a dimer in the asymmetric unit. Both structures show essentially 2-fold molecular symmetry. NAD binding causes movement of the catalytic domain and ordering of the C terminus, where a new helix appears. This completes formation of the enzyme active centre in holo FDH. NAD is bound in the cleft separating the domains and mainly interacts with residues from the co-enzyme binding domain. In apo FDH these residues are held in essentially the same conformation by water molecules occupying the NAD binding region. An azide molecule is located near the point of catalysis, the C4 atom of the nicotinamide moiety of NAD, and overlaps with the proposed formate binding site. There is an extensive channel running from the active site to the protein surface and this is supposed to be used by substrate to reach the active centre after NAD has already bound. The structure of the active site and a hypothetical catalytic mechanism are discussed. Sequence homology of FDH with other NAD-dependent formate dehydrogenases and some D-specific dehydrogenases is discussed on the basis of the FDH three-dimensional structure.
J Mol Biol 1994 Feb 25
PMID:High resolution structures of holo and apo formate dehydrogenase. 811 93

The crystal structures of three forms of Escherichia coli thioredoxin reductase have been refined: the oxidized form of the wild-type enzyme at 2.1 A resolution, a variant containing a cysteine to serine mutation at the active site (Cys138Ser) at 2.0 A resolution, and a complex of this variant with nicotinamide adenine dinucleotide phosphate (NADP+) at 2.3 A resolution. The enzyme mechanism involves the transfer of reducing equivalents from reduced nicotinamide adenine dinucleotide phosphate (NADPH) to a disulfide bond in the enzyme, via a flavin adenine dinucleotide (FAD). Thioredoxin reductase contains FAD and NADPH binding domains that are structurally similar to the corresponding domains of the related enzyme glutathione reductase. The relative orientation of these domains is, however, very different in the two enzymes: when the FAD domains of thioredoxin and glutathione reductases are superimposed, the NADPH domain of one is rotated by 66 degrees with respect to the other. The observed binding mode of NADP+ in thioredoxin reductase is non-productive in that the nicotinamide ring is more than 17 A from the flavin ring system. While in glutathione reductase the redox active disulfide is located in the FAD domain, in thioredoxin reductase it is in the NADPH domain and is part of a four-residue sequence (Cys-Ala-Thr-Cys) that is close in structure to the corresponding region of thioredoxin (Cys-Gly-Pro-Cys), with a root-mean-square deviation of 0.22 A for atoms in the disulfide bonded ring. There are no significant conformational differences between the structure of the wild-type enzyme and that of the Cys138Ser mutant, except that a disulfide bond is not present in the latter. The disulfide bond is positioned productively in this conformation of the enzyme, i.e. it stacks against the flavin ring system in a position that would facilitate its reduction by the flavin. However, the cysteine residues are relatively inaccessible for interaction with the substrate, thioredoxin. These results suggest that thioredoxin reductase must undergo conformational changes during enzyme catalysis. All three structures reported here are for the same conformation of the enzyme and no direct evidence is available as yet for such conformational changes. The simplest possibility is that the NADPH domain rotates between the conformation observed here and an orientation similar to that seen in glutathione reductase. This would alternately place the nicotinamide ring and the disulfide bond near the flavin ring, and expose the cysteine residues for reaction with thioredoxin in the hypothetical conformation.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1994 Feb 25
PMID:Crystal structure of Escherichia coli thioredoxin reductase refined at 2 A resolution. Implications for a large conformational change during catalysis. 811 95

The proliferation of cultured human arterial smooth muscle cells (HASMC) was suppressed by nicotinamide and its analogue, 3-aminobenzamide, in a concentration-dependent manner, based on cell count and [3H]thymidine incorporation into DNA. The addition of 10 and 15 mM nicotinamide, or 6 mM 3-aminobenzamide, to HASMC, for 96 h, resulted in a 19.3%, 44% and 41.5% reduction of cell growth and inhibition of DNA synthesis. Since c-myc protooncogene expression has previously been correlated with cell proliferation, the steady state level of its mRNA was determined in control and treated HSMC by Northern analysis, following a 1 h treatment with the respective chemicals. Whereas c-myc mRNA was suppressed by nicotinamide in proportion to its ability to reduce HASMC growth, down regulation of c-myc by 3-aminobenzamide was much less than the observed antiproliferative effect. These results suggest that the growth regulatory properties of nicotinamide and 3-aminobenzamide in HASMC are probably unrelated to their activity in controlling c-myc gene expression.
Biochem Mol Biol Int 1993 Dec
PMID:The anti-proliferative effects of nicotinamide and 3-aminobenzamide on human smooth muscle cells in vitro. 813 11

Cyclic adenosine diphosphate-ribose, an endogenous metabolite of nicotinamide adenine dinucleotide was first characterized as a potent Ca2+ mobilizing agent in sea urchin eggs. Mounting evidence points to it being an endogenous activator of Ca(2+)-induced Ca2+ release by non-skeletal muscle ryanodine receptors in several invertebrate and mammalian cell types. Cyclic adenosine diphosphate-ribose is synthesized by adenosine diphosphate-ribosyl cyclases, which have been found to be widespread enzymes. Recent data suggests that cyclic adenosine diphosphate-ribose may function as a second messenger in sea urchin eggs at fertilization and in stimulus secretion coupling in pancreatic beta-cells. A second messenger role for cyclic adenosine diphosphate-ribose requires that its intracellular levels be under the control of extracellular stimuli. Another second messenger, cGMP, stimulates the synthesis of cyclic adenosine diphosphate-ribose from nicotinamide adenine dinucleotide by activating the adenosine diphosphate-ribosyl cyclase pathway in sera urchin eggs and egg homogenates, suggesting that cyclic adenosine diphosphate-ribose may be an intracellular messenger for cell surface receptors or nitric oxide, which activate cGMP-producing guanylate cyclases. Cyclic adenosine diphosphate-ribose may have a similar role to inositol trisphosphate in controlling intracellular calcium signalling with these two calcium-mobilizing second messengers activating ryanodine receptors and inositol trisphosphate receptors respectively.
Mol Cell Endocrinol 1994 Jan
PMID:Cyclic ADP-ribose, the ADP-ribosyl cyclase pathway and calcium signalling. 814 21

zeta-Crystallin is a novel nicotinamide adenine dinucleotide phosphate:quinone reductase, present at enzymatic levels in various tissues of different species, which is highly expressed in the lens of some hystricomorph rodents and camelids. We report here the complementary DNA (cDNA) cloning of zeta-crystallin from liver libraries in guinea pig (Cavia porcellus), where zeta-crystallin is highly expressed in the lens, and in the laboratory mouse (Mus musculus), where expression in the lens occurs only at enzymatic levels. A 5' untranslated sequence different from the one previously reported for the guinea pig lens cDNA was found in these clones. We also report the isolation of genomic clones including the complete guinea pig zeta-crystallin gene and the 5' region of this gene in mouse. These results show the presence of two promoters in the guinea pig zeta-crystallin gene, one responsible for expression at enzymatic levels and the other responsible for the high expression in the lens. The guinea pig lens promoter is not present in the mouse gene. This is the first example in which the recruitment of an enzyme as a lens crystallin can be explained by the acquisition of an alternative lens-specific promoter.
Mol Biol Evol 1994 Mar
PMID:Comparative analysis of the zeta-crystallin/quinone reductase gene in guinea pig and mouse. 817 Mar 70


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