Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The naphthoquinone moiety was proven to be essential to the biological activities of sakyomicin A using various naphthoquinone derivatives. Among the naphthoquinones tested, juglone (5-hydroxy-1,4-naphthoquinone) which resembles the partial structure of sakyomicin A was the most active in cytotoxicity against murine lymphosarcoma L5178Y cells, electron acceptor function in the oxidation of NADH by Clostridium kluyveri diaphorase or rat liver mitochondria and inhibition against avian myeloblastosis virus reverse transcriptase. The significantly lower cytotoxicity of sakyomicin A as compared with juglone was attributable to its poor membrane transport. The inhibition of reverse transcriptase activity may result from the interaction between a sulfhydryl group in the active center of the enzyme and quinone groups of the naphthoquinones and sakyomicin A.
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PMID:Role of the naphthoquinone moiety in the biological activities of sakyomicin A. 242 91

Thirteen heterocyclic quinones (5 quinoline quinones, 7 isoquinoline quinones, 1 indole quinone) were tested for their effects on avian myeloblastosis virus reverse transcriptase, growth of murine lymphoblastoma L5178Y cells, respiration of rat liver mitochondria and oxidation of NADH by Clostridium kluyveri diaphorase in comparison with those of streptonigrin, in which the quinoline quinone moiety is considered to play a crucial role. Most of the quinoline quinones and isoquinoline quinones inhibited reverse transcriptase to the same extent as streptonigrin with the ID50 values ranging between 1 and 5 micrograms/ml, whereas the ID50 value of the indole quinone derivative, 4,7-dihydro-2,3-dimethylindole-4,7-dione, was 80 micrograms/ml. The cytotoxicities of the quinones were much lower than that of streptonigrin; the ID50 values of the quinones were higher than 0.15 micrograms/ml. In particular, the ID50 value of the ortho-quinoline quinone derivative, 8-methoxy-7-methyl-5,6-dihydroquinoline-5,6-dione, was as high as 16 micrograms/ml, while the 50% inhibition of cell growth was seen in the presence of 0.0025 micrograms/ml streptonigrin. The membrane transport of the quinones was evaluated by comparing the effects on oxygen consumption by mitochondria and oxidation of NADH by bacterial diaphorase, being proven not to be responsible for their lower cytotoxicities.
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PMID:Comparative study on biological activities of heterocyclic quinones and streptonigrin. 244 Aug 40

Inhibition of avian myeloblastosis virus (AMV) reverse transcriptase by natural and synthetic quinones including antibiotics could be accounted for by an oxidation-reduction reaction. The quinones were shown to function as electron acceptors as revealed by the catalytic oxidation of NADH by Clostridium kluyveri diaphorase which was in excellent agreement with enzyme inhibition activity. The kinetics of inhibition of AMV reverse transcriptase by three synthetic quinones with different core structures, i.e., 6-methoxy-5,8-dihydroquinoline-5,8- dione, 5,8-dihydroisoquinoline-5,8-dione and 1,4-naphthoquinone, were studied. These quinones inhibited reverse transcriptase in the same manner as streptonigrin (STN) and were shown to act at a single class of reaction site(s) on the enzyme molecule. In contrast, the quinones with bulky substituents, i.e., 7-(2-nitrophenethylamino)-5,8-dihydroisoquinoline-5,8-dione and 7-methoxy-6-methyl-3-piperidino-5,8-dihydroisoquinoline-5,8-dione, were inactive as inhibitors of reverse transcriptase, whereas they retained competent catalytic activities in the oxidation of NADH by C. kluyveri diaphorase. Based on these observations, the existence of a specific site of interaction on the enzyme molecule, referred to as a quinone pocket, was proposed. The quinone pocket might play a crucial role in the early sequence of events leading to the inhibition of reverse transcriptase by quinones including STN and sakyomicin A (SKM). Access of SKM to a quinone pocket might be restricted due to its bulky structure in the vicinity of the quinone group. This is inferred from unsuccessful inhibition of reverse transcriptase by the quinones with bulky substituents, resulting in much poorer inhibition of reverse transcriptase in spite of more potent electron acceptor activity in the oxidation-reduction system as compared with those of STN.
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PMID:Mechanism of inhibition of reverse transcriptase by quinone antibiotics. II. Dependence on putative quinone pocket on the enzyme molecule. 246 54

Zidovudine (azidothymidine, AZT), a drug used in acquired immune deficiency syndrome (AIDS), blocks reverse transcriptase and therefore inhibits human immunodeficiency virus (HIV) replication. We carried out an ultrastructural and histoenzymatic study in rat cardiac muscle. Groups of animals (3 rats per group) were given drinking water with or without AZT (1 or 2 mg AZT/ml). After 30, 60 and 120 days, the hearts were studied by light and electron microscopy. Histochemical analysis of isocitrate, succinic, malic, NADH and NADPH dehydrogenase activities revealed no changes in AZT-treated rats compared with control rats. The ultrastructural study showed a disruption of cristae and an increased size of mitochondria in rats treated with AZT for 30- and 60-days. No alterations were observed in rats that received the 120-day treatment. A statistical analysis based on electron micrographs demonstrated a time-dependent ratio between intact and disrupted mitochondria. Rats that received AZT for 30 days showed a higher number of abnormal mitochondria than rats that received the 60 day treatment. No differences with respect to rat controls were observed in the rats that received AZT for 120 days. We conclude that AZT-induced ultrastructural alterations in cardiac muscle did not modify the histochemical activity of several mitochondrial enzymes.
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PMID:Histochemical and ultrastructural changes induced by zidovudine in mitochondria of rat cardiac muscle. 753 28

11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyzes the conversion of active cortisol to inactive cortisone, and regulates the access of cortisol to both the mineralocorticoid and glucocorticoid receptors. Two isoforms of 11 beta-HSD have been described, the cloned "type 1" NADP(H)-dependent dehydrogenase/oxo-reductase and a high affinity NAD-dependent dehydrogenase (type 2). In the fetus, 11 beta-HSD activity may serve to protect developing tissues from cortisol excess or may modulate the permissive actions of glucocorticoids. We have studied 11 beta-HSD activity and mRNA levels in human mid-gestational fetal tissues. Tissue homogenates were incubated with either 0.1 mumol/L cortisol and 400 mumol/L NAD, 2.5 mumol/L cortisol and 400 mumol/L NADP, or 0.1 mumol/L cortisone wither either 400 mumol/L NADPH or NADH. No activity (< 2.5% conversion) was observed in fetal tissues using either cortisone or 2.5 mumol/L cortisol as a substrate. 11-oxo-reductase activity was observed in maternally-derived decidua. In keeping with these activity studies, northern blot analysis of fetal tissue RNA and PCR-reverse transcriptase of type 1 11 beta-HSD mRNA indicated 11 beta-HSD mRNA in decidua, but failed to detect any type 1 11 beta-HSD mRNA transcripts in fetal tissues. In contrast when 0.1 mumol/L cortisol was used as a substrate in the presence of NAD, 11 beta-HSD activity was ubiquitous with highest levels seen in the kidney (131 +/- 16 (SE) pmoles cortisone formed/h/mg.protein) > lung > gonad > liver > colon. 11 beta-HSD activity in fetal tissues is mediated by the type 2, high affinity, isoform. The widespread distribution of this novel isoform suggests that it may play an important role in fetal development. Type 1 11 beta-HSD mRNA and activity are absent in mid-gestational fetal tissues, but present in maternally-derived decidua, suggesting that its ontogeny is a late-gestational of post-natal event.
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PMID:Type 2 11 beta-hydroxysteroid dehydrogenase in human fetal tissues. 820 Sep 59

Intrauterine growth retardation (IUGR) resulting from placental insufficiency is a common complication of pregnancy. Bilateral uterine artery ligation of the pregnant rat is a model which mimics intrauterine growth retardation in the human. IUGR rat fetuses have altered hepatic energy and redox states, with reduced fetal hepatic ATP/ADP ratio, increased cytosolic NAD+/NADH ratio, and decreased mitochondrial NAD+/NADH ratio. These critical changes in energy metabolism contribute to IUGR. The effects of these changes at the molecular level are largely unknown. To address these effects we compared hepatic mRNA populations of IUGR and normal fetuses and neonates using mRNA differential display, a polymerase chain reaction-based method for assaying transcriptional differences under various conditions. We isolated and sequenced 18 cDNA products whose mRNA levels were elevated in IUGR compared with normal fetal and neonatal liver. These analyses demonstrated that NADH-ubiquinone oxireductase subunit 4L mRNA (ND-4L) was significantly increased in liver of IUGR fetuses and neonates. This suggested that IUGR may be associated with altered expression of genes involved in the generation of ATP and NADH. Therefore, we measured mRNA levels of adenine-nucleotide translocator-2 (ANT-2), glucose-6-phosphate dehydrogenase (G6PD), mitochondrial malate dehydrogenase (MMD), ornithine transcarbamylase (OTC), and phosphofructokinase-2 (PFK-2) using a semiquantitative reverse transcriptase-polymerase chain reaction-based technique. In the IUGR fetus, ND-4L, ANT-2, G6PD, and MMD mRNA levels were significantly elevated; PFK-2 mRNA levels were unchanged, and OTC levels were decreased. In the IUGR newborn rat, mRNA levels of all 6 enzymes were increased suggesting that the metabolic state of the growth retarded newborn remains abnormal after birth. Uteroplacental insufficiency affects the immediate and long-term metabolic milieu of the growth retarded animal, and forces specific adjustments, including the expression of mRNA encoding enzymes involved with hepatic energy production.
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PMID:Altered hepatic gene expression of enzymes involved in energy metabolism in the growth-retarded fetal rat. 892 56

Superoxide radical (O2-) is ubiquitously critical to the bioactivity of endothelial nitric oxide. In angiotensin-dependent hypertension, vascular O2- levels rise and impede endothelium/nitric oxide-dependent vascular relaxation. We have reported that the major O2- source in the rabbit aorta is adventitial fibroblast phagocyte-like NADPH oxidase and shown that angiotensin (Ang) II treatment of adventitial fibroblasts causes a concentration-dependent increase in particulate NADPH-dependent O2-. From cultured rabbit aortic adventitial fibroblasts treated or not treated with Ang II, we prepared particulate fractions and measured lucigenin-enhanced chemiluminescence. Because [Sar1,Thr8]-Ang II, a generalized antagonist of Ang II and plausible inhibitor of the conversion of Ang II, reversed Ang II (10 nmol/L)-induced NADH- and NADPH-dependent O2- to basal levels, we tested the effect of the inhibitor of aminopeptidase N, amastatin (10 micromol/L), and found no effect on Ang II-stimulated O2-. Ang(1-7), Ang III, and Ang IV also were not effective in stimulating O2- levels at concentrations similar to those of Ang II. Kinetic analysis showed a rise in NADPH oxidase O2- production in response to Ang II, which peaks at 3 hours and returns to basal levels by 16 hours. p67phox, a cytosolic factor, appears to be affected at both the level of transcription and protein synthesis because actinomycin and cycloheximide individually inhibited the observed effect. A partial sequence of p67phox was recovered by reverse transcriptase from mRNA harvested from cultured rabbit aortic adventitial fibroblasts. Furthermore, the p67phox mRNA transcript in aortic fibroblasts is induced by Ang II before the peak of NADPH oxidase by Northern analysis and ribonuclease protection assays. These data suggest that Ang II stimulates NAD(P)H oxidase O2- generation in fibroblasts of aortic adventitia via transcriptional activation of p67phox. These data also provide preliminary evidence for the regulation of factors of the NADPH oxidase and potentially provide a novel means by which to abrogate the development of O2(-)-dependent hypertension.
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PMID:Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. 971 63

The degradation of synthetic compounds requires bacteria to recruit and adapt enzymes from pathways for naturally occurring compounds. Previous work defined the steps in 2,4-dinitrotoluene (2,4-DNT) metabolism through the ring fission reaction. The results presented here characterize subsequent steps in the pathway that yield the central metabolic intermediates pyruvate and propionyl coenzyme A (CoA). The genes encoding the degradative pathway were identified within a 27-kb region of DNA cloned from Burkholderia cepacia R34, a strain that grows using 2,4-DNT as a sole carbon, energy, and nitrogen source. Genes for the lower pathway in 2,4-DNT degradation were found downstream from dntD, the gene encoding the extradiol ring fission enzyme of the pathway. The region includes genes encoding a CoA-dependent methylmalonate semialdehyde dehydrogenase (dntE), a putative NADH-dependent dehydrogenase (ORF13), and a bifunctional isomerase/hydrolase (dntG). Results from analysis of the gene sequence, reverse transcriptase PCR, and enzyme assays indicated that dntD dntE ORF13 dntG composes an operon that encodes the lower pathway. Additional genes that were uncovered encode the 2,4-DNT dioxygenase (dntAaAbAcAd), methylnitrocatechol monooxygenase (dntB), a putative LysR-type transcriptional (ORF12) regulator, an intradiol ring cleavage enzyme (ORF3), a maleylacetate reductase (ORF10), a complete ABC transport complex (ORF5 to ORF8), a putative methyl-accepting chemoreceptor protein (ORF11), and remnants from two transposable elements. Some of the additional gene products might play as-yet-undefined roles in 2,4-DNT degradation; others appear to remain from recruitment of the neighboring genes. The presence of the transposon remnants and vestigial genes suggests that the pathway for 2,4-DNT degradation evolved relatively recently because the extraneous elements have not been eliminated from the region.
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PMID:Origins of the 2,4-dinitrotoluene pathway. 1210 40

Uridine diphospho-D-glucuronate carboxy-lyase (UDP-D-xylose synthase; EC 4.1.1.35), which catalyzes the conversion of UDP-D-glucuronate to UDP-D-xylose, was purified to apparent homogenity from pea (Pisum sativum L.) seedlings. The pH optimum for enzyme activity was around 5-6, and the activity was not affected by exogeneously supplied NAD+ and NADH. The purified enzyme had a molecular weight of 250 kDa and consisted of 42 kDa polypeptides. Based on the amino acid sequence, a probe (400 bp) was prepared with degenerate primers by a reverse transcriptase-PCR. Using this probe, a clone encoding 346 amino acid residues was screened from a pea cDNA library. The recombinant protein expressed in Escherichia coli catalyzed conversion of UDP-D-glucuronate to UDP-D-xylose, confirming that the isolated clone encoded UDP-D-glucuronate carboxy-lyase.
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PMID:Purification and cDNA cloning of UDP-D-glucuronate carboxy-lyase (UDP-D-xylose synthase) from pea seedlings. 1246 Nov 25

We studied the effect of ageing on the mRNA levels of mitochondria-encoded polypeptides in human platelets. We used quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) to investigate the expression of selected cytochrome c oxidase (COX) genes (subunits I and III) and Complex I genes (subunits reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase (ND)1 and (ND)5 in platelets from young and aged healthy subjects. Northern blot analysis confirmed the PCR results. COX I expression is higher than that of COX III in both young and aged platelets. A significant increase of transcripts for Complex I was found during ageing. On the contrary, the mRNA levels of the two COX subunits did not significantly vary during ageing.
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PMID:Increased transcription of mitochondrial genes for Complex I in human platelets during ageing. 1475 9


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