Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intraperitoneal injections of the nicotinamide antagonist 6-amino-nicotinamide (6-AN) were used to determine if there are regional differences in putative glial energy metabolism between the developing and adult rat CNS. 6-AN shuts down the hexose monophosphate pathway, which is used preferentially by astrocytes and oligodendrocytes. These cells subsequently undergo cytotoxic edema and cell death. Adult rats and pups ranging in age from 7 to 31 d received a single injection of 6-AN and were sacrificed after 24 h. As demonstrated wit immunocytochemical staining for the astroglia-specific markers GFAP and S-100 beta, the 7-9-d-old animals exhibited a uniform appearance with edematous glial cells located throughout the CNS. However, with advancing age, a consistent pattern of progressively decreasing amounts of injured glia, which has not been previously described, occurred in cerebral and cerebellar structures. After 3 wk postnatal, the adult pattern was manifested in which glial degeneration occurred only in specific regions of the spinal cord, cerebellum, medulla, and thalamus, whereas the remainder of the CNS appeared normal. The results suggest the presence of heterogeneous populations of glia whose preferred use of the hexose monophosphate pathway is predicated on both the age of the animal and their location in the CNS.
Mol Chem Neuropathol 1995 Oct
PMID:Age-dependent susceptibility of CNS glial populations in situ to the antimetabolite 6-aminonicotinamide. 857 44

Basic fibroblast growth factor (FGF-2) is posttranslationally modified by the enzymatic transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD). When sonicated nuclei of adrenal capillary endothelial or SK-Hep1 cells are incubated with [32P]NAD, FGF-2 is rapidly ADP-ribosylated in a dose- and time-dependent fashion. Proteins structurally related to FGF-2 (FGF-6 and -7) are readily modified, suggesting that they share a common substrate motif. Yet, FGF-1, the most structurally homologous member of the FGF family, is a poor substrate. The reaction is also specific; interleukin-1 alpha, transforming growth factor-alpha, nerve growth factor, insulin-like growth factor-I, and granulocyte macrophage-colony stimulating factor are not substrates for ribosylation. Because the ADP ribosylation of FGF-2 is acid resistant but base and hydroxylamine sensitive, the linkage appears to be mediated through arginine. Most importantly, however, we also establish that endogenous FGF-2 is a substrate for ribosylation. As such, an immunoreactive ADP-ribosylated FGF-2 is detected in extracts of SK-Hep1 nuclei when they are incubated with [32P]NAD. Taken together, these findings suggest that the role played by ADP ribosylation in signal transduction, DNA repair, the control of the cell cycle, and cell differentiation may involve its ability to target molecules such as FGF-2.
Mol Endocrinol 1995 Jun
PMID:Adenosine diphosphate ribosylation of fibroblast growth factor-2. 859 22

Nitric oxide (NO) has been proposed as a possible mediator of beta-cell damage in human IDDM. This hypothesis is based on in vitro studies with rodent pancreatic islets. In the present study we examined whether human beta-cells are affected by NO. In view of species differences in beta-cell sensitivity to damaging agents, rat islets were investigated in parallel. Isolated islets were exposed for 90 min to different concentrations of three chemically unrelated NO donors, SIN-1, GSNO or RBS. At the end of this incubation, human insulin release was mostly similar in control and NO-treated islets but, 48 h later, islet retrieval, islet DNA and insulin content, and glucose-induced insulin release were markedly lower in islets exposed to NO donors. Rat islets were already inhibited during the initial 90 min; 48 h later their loss in beta-cell function was similar to that in human islets. Nicotinamide or succinic acid monomethyl ester partially protected against SIN-1 induced islet cell loss, but not against the functional inhibition of human pancreatic islets. Exposure of human or rat islets to RBS was associated with significant DNA strand breakage, as judged by the comet assay (single cell gel electrophoresis) and by ultrastructural signs of cell damage. DNA damage was more severe in rat islet cells exposed to similar amounts of RBS. It is concluded that NO donors can damage human pancreatic islets, an effect paralleled by induction of nuclear DNA strand breaks.
Mol Cell Endocrinol 1996 Apr 19
PMID:Nitric oxide donors decrease the function and survival of human pancreatic islets. 873 93

The individual fluorescence and phosphorescence properties of W84 and W310 in Bacillus stearothermophilus glyceraldehyde-3-phosphate dehydrogenase were identified through the construction of a single tryptophan mutant (W84F) and by comparison of the emission between mutant and wild-type enzymes. The results show that the luminescence of W310 is red-shifted and substantially quenched relative to that of W84. It displays an average subnanosecond fluorescence lifetime (tau F) and a very short, 50 microseconds, room-temperature phosphorescence (RTP) lifetime (tau P). The perturbation of W310 luminescence is believed to arise from a stacking interaction with Y283. In contrast, W84 exhibits a fluorescence lifetime tau F of several nanoseconds and a long-lived phosphorescence lifetime tau P, typical of buried, unperturbed TrP residues. NAD+ binding to the tetrameric enzyme causes a 55% reduction of W310 fluorescence intensity together with a nearly complete quenching of its low-temperature phosphorescence. W84, which is located far from the nicotinamide moiety of NAD+, is much less affected by the binding of the coenzyme; the reduction in fluorescence intensity is 35%, and its phosphorescence intensity is unchanged. Another consequence of NAD+ binding is a significant decrease of the RTP lifetime tau P of W84, manifesting thereby a conformational change in the region of the coenzyme-binding domain. However, no change is observed in the RTP lifetime tau P of W310 located in the catalytic domain. These findings and those obtained at partial coenzyme saturation support the conclusions derived from high-resolution crystallographic structures [Skarzynski, T., & Wonacott, A. J., (1988) J. Mol. Biol. 203, 1097-1118] that the NAD(+)-induced conformational change is sequential and that subtle rearrangement in the structure of unligated subunits might be responsible for the negative cooperative behavior of NAD+ binding.
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PMID:Effects of NAD+ binding on the luminescence of tryptophans 84 and 310 of glyceraldehyde-3-phosphate dehydrogenase from Bacillus stearothermophilus. 882 92

In order to gain some insight into the mechanism by which nicotinamide nucleotides localize in mitochondria, NMN was added to rat liver mitochondria, with NAD synthesis tested both enzymatically and by means of HPLC. Evidence is given that the mitochondrial matrix contains a specific NMN adenylyltransferase (E.C. 2.7.7.1.), inhibited by PPi, AMP and ADP-ribose. Some features of this enzyme, including the substrate, pH and temperature dependence were also investigated.
Biochem Mol Biol Int 1996 Feb
PMID:Rat liver mitochondria can synthesize nicotinamide adenine dinucleotide from nicotinamide mononucleotide and ATP via a putative matrix nicotinamide mononucleotide adenylyltransferase. 885 May 25

The crystal structure of the ferredoxin:NADP+ reductase (FNR) from the cyanobacterium Anabaena PCC 7119 has been determined at 2.6 A resolution by multiple isomorphous replacement and refined using 15.0 A to 1.8 A data, collected at 4 degrees C, to an R-factor of 0.172. The model includes 303 residues, the flavin adenine dinucleotide cofactor (FAD), one sulfate ion located at the putative NADP+ binding site and 328 water molecule sites. The structure of Anabaena FNR, including FAD, a network of intrinsic water molecules and a large hydrophobic cavity in the C-terminal domain, resembles that of the spinach enzyme. The major differences concern the additional short alpha-helix (residues 172 to 177 in Anabaena FNR) and residues Arg 100 and Arg 233 which binds NADP+ instead of Lys 116 and Lys 244 in the spinach enzyme. Crystals of a complex of Anabaena FNR with NADP+ were obtained. The model of the complex has been refined using 15 A to 2.25 A X-ray data, collected at -170 degrees C, to an R-factor of 0.186. This model includes 295 residues, FAD, the full NADP+ (with an occupancy of 0.8) and 444 water molecules. The 2'-5' adenine moiety of NADP+ binds to the protein as 2'-phospho-5'-AMP to the spinach FNR. The nicotinamide moiety is turned towards the surface of the protein instead of stacking onto the FAD isoalloxazine ring as would be required for hydride transfer. The model of the complex agrees with previous biochemical studies as residues Arg 100 and Arg 233 are involved in NADP+ binding and residues Arg77, Lys 53 and Lys 294, located on the FAD side of the enzyme, remain free to interact with ferredoxin and flavodoxin, the physiological partners of ferredoxin: NADP reductase.
J Mol Biol 1996 Oct 18
PMID:X-ray structure of the ferredoxin:NADP+ reductase from the cyanobacterium Anabaena PCC 7119 at 1.8 A resolution, and crystallographic studies of NADP+ binding at 2.25 A resolution. 889 Sep 10

The effect of nicotinamide on the streptozocin induced early hyperglycaemia in 48-hour fasted rats was investigated. It was shown that 240 or 400 mg/kg nicotinamide significantly attenuated the streptozocin induced early hyperglycaemia. Nicotinamide should be administered no later than 1 hour after the streptozocin administration. Lower level doses of nicotinamide such as 80 mg/kg were unable to attenuate the streptozocin induced early hyperglycaemia. The possibility of nicotinamide offsetting the streptozocin effect was discussed.
Biochem Mol Biol Int 1996 Oct
PMID:Attenuation by nicotinamide of the streptozocin induced early hyperglycaemia in fasting rats. 890 60

The pineal hormone melatonin modulates constitutive protein secretion from murine melanoma M2R cells in vitro, in a cholera-toxin (CTX)-sensitive process, without effecting major changes in cAMP. The effects of melatonin on GTP binding proteins and putative CTX substrates in these cells were investigated. Melatonin enhanced GTP gamma 35S binding and the incorporation of 32P-P3-(4-azidoanilido)-P1-5'-guanosine triphosphate (Az-32P-GTP) into 94, 40 and 28 kilodalton proteins. Similar changes were induced by CTX treatment. In addition, melatonin enhanced ADP ribosylation of several proteins, among them 94 and 40 kilodalton bands, apparently at arginyl residues. CTX catalyzed the ADP ribosylation of 45 and 40 (both recognized by antibodies specific to the C-terminal peptide of the Gs alpha subunit) and 94 kilodalton proteins and attenuated melatonin's effect. The melatonin-mediated ADP ribosylation reactions were attenuated by nicotinamide which inhibits mono(ADP ribosyl)transferases and poly(ADP-ribose)synthetase, but not by 3-amino benzamide, a specific inhibitor of poly(ADP-ribose)synthetase. Nicotinamide but not 3-amino benzamide prevented the enhancement by melatonin of GTP gamma 35S binding. These results indicate that melatonin enhances protein ADP ribosylation and consequently GTP exchange in a number of CTX-sensitive G proteins. They demonstrate a novel route for concerted activation of multiple GTP binding proteins by a single hormone.
Mol Cell Endocrinol 1996 Oct 30
PMID:Enhancement by melatonin of GTP exchange and ADP ribosylation reactions. 896 Dec 51

Salicylic acid (SA) plays an important signaling role in the resistance of many plants to pathogen invasion. Increases in endogenous SA levels have been associated with the hypersensitive response as well as systemic acquired resistance (SAR). SA also induces the expression of a subset of the pathogenesis-related (PR) genes. However, relatively little is known about the events occurring subsequent to SA accumulation during a resistance response. In order to identify mutations in components of the SA signal transduction pathway, we have developed a genetic screen in Arabidopsis thaliana that utilizes the Agrobacterium tumefaciens tms2 gene as a counter-selectable marker. SA-inducible expression of the tms2 gene from the tobacco PR-1a promoter confers sensitivity to alpha-naphthalene acetamide (alpha-NAM), resulting in inhibition of root growth in germinating transgenic Arabidopsis seedlings. Mutants in which root growth is insensitive to alpha-NAM have been selected from this PR-1a:tms2 transgenic line with the expectation that a subset will lack a regulatory component downstream of SA. The sail mutant so identified expressed neither the PR-1a:tms2 transgene nor the endogenous Arabidopsis PR-1, PR-2, and PR-5 genes in response to SA. These genes also were not induced in sai1 by 2,6-dichloroisonicotinic acid (INA) or benzothiadiazole (BTH), two chemical inducers of SAR. As expected of a mutation acting downstream of SA, sai1 plants accumulate SA and its glucoside in response to infection with an avirulent pathogen and are more susceptible to this avirulent pathogen than the wild-type parent. sai1 is allelic to npr1, a previously identified SA-noninducible mutation. The recessive nature of the noninducible sai1 mutation suggests that the wild-type SAI1 gene acts as a positive regulator in the SA signal transduction pathway.
Mol Plant Microbe Interact 1997 Jan
PMID:Characterization of a salicylic acid-insensitive mutant (sai1) of Arabidopsis thaliana, identified in a selective screen utilizing the SA-inducible expression of the tms2 gene. 900 72

A single amino acid substitution, Phe98 to Tyr98, in dihydrofolate reductase (DHFR) is the molecular origin of trimethoprim (TMP) resistance in Staphylococcus aureus. This active site amino acid substitution was found in all S. aureus TMP-resistant clinical isolates tested. In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography. Critical evidence concerning the resistance mechanism has also been provided by NMR spectral analyses of 15N-labelled TMP in the ternary complexes of both wild-type and mutant enzyme. These studies show that the mutation results in loss of a hydrogen bond between the 4-amino group of TMP and the carbonyl oxygen of Leu5. This mechanism of resistance is predominant in both transferable plasmid-encoded and non-transferable chromosomally encoded resistance. Knowledge of the resistance mechanism at a molecular level could help in the design of antibacterials active against multi-resistant Staphylococcus aureus (MRSA), one of todays most serious problems in clinical infectology.
J Mol Biol 1997 Feb 14
PMID:A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance. 905 67


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