Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.5 (RNase)
17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose) (polymer) is enzymatically synthesized on nuclear proteins in response to DNA strand breaks. NAD+ is the substrate for this reaction, which is catalyzed by poly(ADP-ribose)polymerase. This post-translational modification occurs in response to DNA strand breaks and is thought to play an important role in DNA repair. Polymer synthesis resulting from DNA damage has been described in cultured cells, but measurement is more difficult in animal tissues. In this study, modifications were made to an earlier method to measure carcinogen-induced increases in polymer levels in vivo. RNase I was added to the enzyme mixture used to digest polymer to ribosyladenosine (RAdo). This prevented the inhibition of snake venom phosphodiesterase by RNA. The HPLC analysis was improved, allowing elimination of the second boronate affinity chromatography step traditionally used to purify epsilon RAdo. Using this technique, we have studied the effect of i.p. diethylnitrosamine (DEN) injection on hepatic NAD+ and poly(ADP-ribose) levels in Fischer-344 rats. Hepatic polymer levels rose 8-fold from 26 to 218 pmol/g liver wet weight, 10 h following 200 mg DEN/kg body weight (n = 4-5). Liver NAD+ decreased concurrently, to 61% of basal levels at 16 h post-treatment (n = 4-5). Erythrocyte NAD+ concentrations remained unchanged, despite carcinogen administration. The DEN-induced effects on tissue polymer and NAD+ levels were dose dependent from 0 to 200 mg DEN/kg body weight (n = 4).
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PMID:Diethylnitrosamine administration in vivo increases hepatic poly(ADP-ribose) levels in rats: results of a modified technique for poly(ADP-ribose) measurement. 826 20

The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-Isomerase (3 beta HSD) catalyzes the conversion of delta 5-3 beta-hydroxysteroids to delta 4-3-ketosteroids, an essential step in the biosynthesis of all biologically active steroid hormones. We previously reported the isolation of three distinct mouse cDNAs for 3 beta HSD (3 beta HSD I, II, and III) and tissue-specific expression of their mRNAs. 3 beta HSD I is expressed only in gonads and adrenal glands, and 3 beta HSD II and III are expressed in both liver and kidneys. In the current study, we present data which demonstrate that transiently expressed 3 beta HSD I and 3 beta HSD III proteins can catalyze the conversion of the delta 5-steroids, pregnenolone and dehydroepiandrosterone, to their respective delta 4-3-ketosteroids, progesterone and androstenedione. They also can dehydrogenate the 3 beta-hydroxy group of the 5 alpha-reduced steroid 5 alpha-androstanediol to yield dihydrotestosterone in the presence of the cofactor NAD+. The Km values of the expressed 3 beta HSD I (for each of these substrates) were all below 0.2 microM. Km values of 3 beta HSD III were greater for all substrates, with the greatest increase observed for pregnenolone, which was over 10-fold greater. Both forms of expressed protein can catalyze the reduction of dihydrotestosterone to 5 alpha-androstanediol in the presence of the cofactor NADH, but with considerably higher Km values (5.5 microM for form I and 6.8 microM for form III). The observed maximum velocity of form I was much higher for all substrates examined. RNase protection and immunoblot analysis of expressed 3 beta HSD I and III indicate that the difference in maximum velocity reflect differences in the steady state levels of mRNA and amounts of protein. In addition, the expressed 3 beta HSD III protein analyzed by Western blot has a lower mobility than the 3 beta HSD I protein, both similar in mol wt to the 3 beta HSD proteins detected in mouse liver and adrenal glands, respectively. These data demonstrate that an isoform of 3 beta HSD expressed in liver and kidney has the capacity to convert delta 5-3 beta-hydroxysteroids to delta 4-3-ketosteroids. The data suggest that a homologous human 3 beta HSD isoform could play an important role in cases of genetic deficiency of the gonadal and adrenal isoform.
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PMID:Enzyme characteristics of two distinct forms of mouse 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase complementary deoxyribonucleic acids expressed in COS-1 cells. 847 48

Isoelectric focusing of MCF-7 cell extracts revealed an association of the glycolytic enzymes glyceraldehyde 3-phosphate-dehydrogenase, phosphoglycerate kinase, enolase, and pyruvate kinase. This complex between the glycolytic enzymes is sensitive to RNase. p36 could not be detected within this association of glycolytic enzymes; however an association of p36 with a specific form of malate dehydrogenase was found. In MCF-7 cells three forms of malate dehydrogenase can be detected by isoelectric focusing: the mitochondrial form with an isoelectric point between 8.9 and 9.5, the cytosolic form with pl 5.0, and a p36-associated form with pl 7.8. The mitochondrial form comprises the mature mitochondrial isoenzyme (pl 9.5) and its precursor form (pl 8.9). Refocusing of the pl 7.8 form of malate dehydrogenase also gave rise to the mitochondrial isoenzyme. Thus, the pl 7.8 form of malate dehydrogenase is actually the mitochondrial isoenzyme retained in the cytosol by the association with p36. Addition of fructose 1,6-bisphosphate to the initial focusing column induced a quantitative shift of the pl 7.8 form of malate dehydrogenase to the mitochondrial forms (pl 8.9 and 9.5). In MCF-7 cells p36 is not phosphorylated in tyrosine. Kinetic measurements revealed that the pl 7.8 form of malate dehydrogenase has the lowest affinity for NADH. Compared to both mitochondrial forms the cytosolic isoenzyme has a high capacity when measured in the NAD --> NADH direction (malate --> oxaloacetate direction). The association of p36 with the mitochondrial isoenzyme may favor the flow of hydrogen from the cytosol into the mitochondria. Inhibition of cell proliferation by AMP which leads to an inhibition of glycolysis has no effect on complex formation by glycolytic and glutaminolytic enzymes in MCF-7 cells. AMP treatment leads to an activation of malate dehydrogenase, which correlates with the increase of pyruvate and the decrease of lactate levels, but has no effect on the distribution of the various malate dehydrogenase forms.
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PMID:Studies on associations of glycolytic and glutaminolytic enzymes in MCF-7 cells: role of P36. 861 64

Labeling of 21-kDa material was observed when bovine brain soluble fraction was incubated with [adenylate-32P]NAD+ in the presence of GTP. The 21-kDa substrate, slightly smaller than C3 substrate in size, was labeled even without C3 exoenzyme. GTP could be replaced by nucleoside triphosphates other than ATP while ATP inhibited the GTP-induced labeling of 21-kDa substrate. After incubation of the soluble fraction with [adenylate-32P]NAD+ in the presence of GTP, [32P]ADP and [32P]ATP were detected in addition to [32P]AMP and [32P]ADP-ribose while only the last two nucleotides were observed without GTP. The 21-kDa substrate was labeled with [alpha-32P]ATP even in the absence of GTP, suggesting adenylylation rather than ADP-ribosylation. The labeled 21-kDa substrate, was extractable by phenol, disappeared with RNase treatment but not with tryptic digestion. Alkaline treatment of the phenol extract yielded an equal mixture of 3'-[32P]CMP and 2'-[32P]CMP. From these results we concluded that the 21-kDa labeling is a result of tRNA tailing with [alpha-32P]ATP generated from the [32P]AMP moiety of [adenylate-32P]NAD+. Results from reconstitution experiments using enzymes and tRNA purified from bovine brain soluble fraction, which are involved in this pathway, confirmed our conclusion.
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PMID:GTP-dependent modification of a 21-kDa substrate with NAD+ in bovine brain soluble fraction is not ADP-ribosylation of small G-protein but tailing of tRNA. 935 90

We hypothesize that poly (ADP-ribosyl)ation, that is, poly (ADP-ribose) polymerase (PARP)-dependent transfer of ADP-ribose moieties from NAD to nuclear proteins, plays a role in diabetic nephropathy. We evaluated whether PARP activation is present and whether two unrelated PARP inhibitors, 3-aminobenzamide (ABA) and 1,5-isoquinolinediol (ISO), counteract overexpression of endothelin-1 (ET-1) and ET receptors in the renal cortex in short-term diabetes. The studies were performed in control rats and streptozotocin-diabetic rats treated with/without ABA or ISO (30 and 3 mg x kg(-1) x day(-1), intraperitoneally, for 2 weeks after 2 weeks of diabetes). Poly (ADP-ribose) immunoreactivity was increased in tubuli, but not glomeruli, of diabetic rats and this increase was corrected by ISO, whereas ABA had a weaker effect. ET-1 concentration (ELISA) was increased in diabetic rats, and this elevation was blunted by ISO. ET-1, ET(A), and ET(B) mRNA (ribonuclease protection assay), but not ET-3 mRNA (RT/PCR), abundance was increased in diabetic rats, and three variables were, at least, partially corrected by ISO. ABA produced a trend towards normalization of ET-1 concentration and ET-1, ET(A), and ET(B) mRNA abundance, but the differences with untreated diabetic group were not significant. Poly(ADP-ribosyl)ation is involved in diabetes-induced renal overexpression of ET-1 and ET receptors. PARP inhibitors could provide a novel therapeutic approach for diabetic complications including nephropathy, and other diseases that involve the endothelin system.
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PMID:Diabetes-induced overexpression of endothelin-1 and endothelin receptors in the rat renal cortex is mediated via poly(ADP-ribose) polymerase activation. 1282 90

We hypothesize that poly(ADP-ribose) polymerase (PARP) activation is an important mechanism in the oxidative stress-related development of diabetic retinopathy. In the experiments reported here, we evaluated if: a) PARP activation is present in the retina in short-term diabetes; and b) PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, counteract diabetes- and hypoxia-induced retinal VEGF formation. In vivo studies were performed in control and streptozotocin-diabetic rats treated with/without 3-aminobenzamide or 1,5-isoquinolinediol (30 and 3 mg/kg per day, intraperitoneally, for 2 weeks after 2 weeks of diabetes). In vitro studies were performed in human retinal pigment epithelial cells exposed to normoxia or hypoxia with/without 3-aminobenzamide and 1,5-isoquinolinediol at 200 and 2 micro M. Retinal immunostaining for poly(ADP-ribose) was increased and NAD concentration reduced in diabetic rats, and both variables were corrected by PARP inhibitors. Retinal VEGF protein (ELISA, immunohistochemistry), but not mRNA (ribonuclease protection assay) abundance, was increased in diabetic rats, and this increase was corrected by both 3-aminobenzamide and 1,5-isoquinolinediol. PARP inhibitors did not affect retinal glucose, sorbitol pathway intermediates or lipid peroxidation in diabetic rats. Hypoxia caused a several-fold increase in both VEGF-mRNA and protein in retinal pigment epithelial cells. VEGF mRNA overexpression was only slighly blunted by PARP inhibitors whereas VEGF protein was corrected. In conclusion, PARP is involved in diabetes- and hypoxia-induced VEGF production at post-transcriptional level, downstream from the sorbitol pathway activation and oxidative stress. The results justify studies of PARP inhibitors in models of retinopathy of prematurity and diabetic retinopathy.
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PMID:Poly(ADP-ribose) polymerase inhibitors counteract diabetes- and hypoxia-induced retinal vascular endothelial growth factor overexpression. 1520 16

Pseudomonas aeruginosa phage EL is a dsDNA phage related to the giant phiKZ-like Myoviridae. The EL genome sequence comprises 211,215 bp and has 201 predicted open reading frames (ORFs). The EL genome does not share DNA sequence homology with other viruses and micro-organisms sequenced to date. However, one-third of the predicted EL gene products (gps) shares similarity (Blast alignments of 17-55% amino acid identity) with phiKZ proteins. Comparative EL and phiKZ genomics reveals that these giant phages are an example of substantially diverged genetic mosaics. Based on the position of similar EL and phiKZ predicted gene products, five genome regions can be delineated in EL, four of which are relatively conserved between EL and phiKZ. Region IV, a 17.7 kb genome region with 28 predicted ORFs, is unique to EL. Fourteen EL ORFs have been assigned a putative function based on protein similarity. Assigned proteins are involved in DNA replication and nucleotide metabolism (NAD+-dependent DNA ligase, ribonuclease HI, helicase, thymidylate kinase), host lysis and particle structure. EL-gp146 is the first chaperonin GroEL sequence identified in a viral genome. Besides a putative transposase, EL harbours predicted mobile endonucleases related to H-N-H and LAGLIDADG homing endonucleases associated with group I intron and intein intervening sequences.
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PMID:Genome comparison of Pseudomonas aeruginosa large phages. 1625 35

1. ADP, ATP and GDP inhibited the phosphotransferase activity, the release of cyclic nucleotides from RNA, of ribonuclease. No significant inhibition was elicited by pyrimidine 5'-nucleoside diphosphates, CDP and UDP. 2. Inhibition by ADP, AMP, adenosine, adenine, NAD and NADP was insignificant at the concentrations tested. Small inhibition was observed with high concentrations of AMP and only when soluble RNA was the substrate. 3. Inhibition by ADP was found to be ;uncompetitive'. 4. Results seem to indicate that at least for optimum inhibition the polyphosphate of the purine nucleoside is essential. They further suggest that the inhibitor acts by combining with the enzyme only when the enzyme is bound to the substrate.
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PMID:Effect of nucleoside 5'-di- and 5'-tri-phosphates on pancreatic ribonuclease activity. 1674 35

Metabolic enzymes are usually characterized to have one specific function, and this is the case of UDP-glucose dehydrogenase that catalyzes the twofold NAD(+)-dependent oxidation of UDP-glucose into UDP-glucuronic acid. We have determined that this enzyme is also capable of participating in other cellular processes. Here, we report that the bacterial UDP-glucose dehydrogenase (UgdG) from Sphingomonas elodea ATCC 31461, which provides UDP-glucuronic acid for the synthesis of the exopolysaccharide gellan, is not only able to bind RNA but also acts as a ribonuclease. The ribonucleolytic activity occurs independently of the presence of NAD(+) and the RNA binding site does not coincide with the NAD(+) binding region. We have also performed the kinetics of interaction between UgdG and RNA. Moreover, computer analysis reveals that the N- and C-terminal domains of UgdG share structural features with ancient mitochondrial ribonucleases named MAR. MARs are present in lower eukaryotic microorganisms, have a Rossmannoid-fold and belong to the isochorismatase superfamily. This observation reinforces that the Rossmann structural motifs found in NAD(+)-dependent dehydrogenases can have a dual function working as a nucleotide cofactor binding domain and as a ribonuclease.
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PMID:Rossmann-fold motifs can confer multiple functions to metabolic enzymes: RNA binding and ribonuclease activity of a UDP-glucose dehydrogenase. 2313 39

RsaE is the only known trans-acting small regulatory RNA (sRNA) besides the ubiquitous 6S RNA that is conserved between the human pathogen Staphylococcus aureus and the soil-dwelling Firmicute Bacillus subtilis. Although a number of RsaE targets are known in S. aureus, neither the environmental signals that lead to its expression nor its physiological role are known. Here we show that expression of the B. subtilis homolog of RsaE is regulated by the presence of nitric oxide (NO) in the cellular milieu. Control of expression by NO is dependent on the ResDE two-component system in B. subtilis and we determined that the same is true in S. aureus. Transcriptome and proteome analyses revealed that many genes with functions related to oxidative stress and oxidation-reduction reactions were up-regulated in a B. subtilis strain lacking this sRNA. We have thus renamed it RoxS. The prediction of RoxS-dependent mRNA targets also suggested a significant enrichment for mRNAs related to respiration and electron transfer. Among the potential direct mRNA targets, we have validated the ppnKB mRNA, encoding an NAD+/NADH kinase, both in vivo and in vitro. RoxS controls both translation initiation and the stability of this transcript, in the latter case via two independent pathways implicating RNase Y and RNase III. Furthermore, RNase Y intervenes at an additional level by processing the 5' end of the RoxS sRNA removing about 20 nucleotides. Processing of RoxS allows it to interact more efficiently with a second target, the sucCD mRNA, encoding succinyl-CoA synthase, thus expanding the repertoire of targets recognized by this sRNA.
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PMID:A nitric oxide regulated small RNA controls expression of genes involved in redox homeostasis in Bacillus subtilis. 2564 72


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