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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bc1 complex of the mitochondrial respiratory chain transfers electrons from ubiquinol to cytochrome c oxidase. Cytochrome b, a transmembranous protein, is thought to form a transmembrane electron circuit, transferring electrons between two ubiquinone redox sites, (Qi) and (Qo), respectively, near the inner and outer sides of the inner mitochondrial membrane. Antimycin and diuron appear to block cytochrome b oxidation-reduction at one ubiquinone site, presumably Qi. The cytochrome b gene is carried by the organelle DNA. Yeast mutants resistant to antimycin and diuron have been previously isolated and mapped to specific loci of the cytochrome b gene. In the present work the mutated amino acid residues from nine antimycin- and three diuron-resistant mutants have been identified by sequencing the relevant segments of the resistant cytochrome b gene. The sequencings were performed by primer extension in the presence of dideoxynucleotides on total mitochondrial RNA preparations using reverse transcriptase. Regions of the cytochrome b protein affecting the inhibitor and putative quinone-binding sites have been defined.
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PMID:Molecular basis for resistance to antimycin and diuron, Q-cycle inhibitors acting at the Qi site in the mitochondrial ubiquinol-cytochrome c reductase in Saccharomyces cerevisiae. 284 35

The human COX5B gene encodes subunit Vb of cytochrome c oxidase (COX). COX Vb is 1 of the 10 subunits of the mitochondrial COX complex encoded by a nuclear gene. We have defined a region in the human COX5B promoter essential for gene expression and shown by phylogenetic footprinting of 11 primate COX5B promoters that many cis-regulatory elements in this region are evolutionarily conserved. The transcription start site of human COX5B was mapped 58 bp upstream of the initiation Met codon by primer extension using a thermostable reverse transcriptase. A 475-bp region (-456 to +20) of the human COX5B gene was shown to function as a promoter for the chloramphenicol acetyl transferase (CAT) gene in expression vectors when transfected into HeLa cells. The human COX5B gene is located in a CpG island and contains several potential binding sites for the transcription factor Sp1, but no consensus TATA box element. Several sequence elements associated with the transcriptional regulation of respiratory genes were also found in the promoter and 5' flanking region, including a single NRF-1 site and two 9-bp direct repeats containing binding sites for ets-domain proteins, such as NRF-2/GABP. Many features of the human COX5B promoter are conserved in the COX5B promoters of primates, in particular, the presence of a single binding site for NRF-1 and multiple sites for Sp1 and NRF-2/GABP. Electrophoretic mobility shift assays demonstrate that the conserved NRF-1 site in primate COX5B promoters is specifically recognized by a factor present in HeLa nuclear extracts. Phylogenetic footprinting has identified additional conserved elements that may also function as binding sites for regulatory factors.
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PMID:Phylogenetic footprinting of the human cytochrome c oxidase subunit VB promoter. 880 66

Plant mitochondrial genomes are highly recombinogenic, with a variety of species-specific direct and inverted repeats leading to in vivo accumulation of multiple DNA forms. In maize, the cox2 gene, which encodes subunit II of cytochrome c oxidase, lies immediately downstream of a 0.7-kilobase direct repeat, which is present in two copies in the 570-kilobase master chromosome. Promoters for cox2 exist upstream of both of these copies, in regions we have termed A and B. Three region B promoters are active for cox2 transcription in the master chromosome, whereas two region A promoters are active for cox2 transcription after recombination across the direct repeats. We have measured the proportion of genomes carrying region A or B upstream of cox2 in maize seedlings and found a ratio of approximately 1:6. Promoter strength, based on run-on transcription assays, shows a ratio of 1:4 for region A to region B promoters. These data allowed us to predict the relative contributions of region A and B to mitochondrial transcript accumulation, based on a simple product of genome-form abundance and promoter strength. When promoter use was determined by using quantitative reverse transcriptase-PCR, however, we found that region A promoters were used at an unexpectedly high rate when upstream of cox2 and used less than expected when not upstream of cox2. Thus, the use of this set of promoters seems to respond to genomic context. These results suggest a role for intragenomic and intergenomic recombination in regulating plant mitochondrial gene expression.
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PMID:Genomic context influences the activity of maize mitochondrial cox2 promoters. 1050 Feb 35

Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in human immunodeficiency virus (HIV)-infected patients treated with the nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir, a nucleotide analog recently approved for use in the treatment of HIV infection, was evaluated in vitro for its potential to cause mitochondrial toxicity and was compared to currently used NRTIs. Treatment with tenofovir (3 to 300 microM) for up to 3 weeks produced no significant changes in mitochondrial DNA (mtDNA) levels in human hepatoblastoma (HepG2) cells, skeletal muscle cells (SkMCs), or renal proximal tubule epithelial cells. The potencies of inhibition of mtDNA synthesis by the NRTIs tested were zalcitabine (ddC) > didanosine (ddI) > stavudine > zidovudine (ZDV) > lamivudine = abacavir = tenofovir, with comparable relative effects in the three cell types. Unlike ddC and ddI, tenofovir did not affect cellular expression of COX II and COX IV, two components of the mitochondrial cytochrome c oxidase complex. Lactate production was elevated by less than 20% in HepG2 cells or SkMCs following treatment with 300 microM tenofovir. In contrast, lactate synthesis increased by >200% in the presence of 300 microM ZDV. Thus, treatment of various human cell types with tenofovir at concentrations that greatly exceed those required for it both to have in vitro anti-HIV type 1 activity in peripheral blood mononuclear cells (50% effective concentration, 0.2 microM) and to achieve therapeutically relevant levels in plasma (maximum concentrations in plasma, 0.8 to 1.3 microM) is not associated with mitochondrial toxicity.
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PMID:Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. 1185 Feb 53

A decreased sperm motility has been reported in men treated with nucleoside analog reverse transcriptase inhibitors (NRTI). Sperm motility is correlated with enzymatic activities of the sperm mitochondrial respiratory chain (MRC), which may be impaired by NRTI. We compared sperm and skeletal muscle MRC and citrate synthase (CS) activities, sperm adenosine triphosphate (ATP) content and sperm motility between rats exposed to zidovudine (AZT) for 10 weeks and controls. Decreased levels of CS-normalized cytochrome c oxidase (COX, the MRC complex IV) activity were observed in the spermatozoa from AZT-treated rats, with no significant decrease in ATP content or motility. In muscle absolute COX activity increased after exposure to AZT but CS-normalized COX activity remained unchanged. These results suggest that exposure to NRTI can induce MRC dysfunction earlier in spermatozoa than in skeletal muscle.
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PMID:Deficit in cytochrome c oxidase activity induced in rat sperm mitochondria by in vivo exposure to zidovudine. 1451 Dec 19

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

Cardiac toxicity has been associated with HIV infection and exposure to nucleoside reverse transcriptase inhibitors (NRTIs), but the role of the latter in the development of cardiac disease of HIV-infected patients is uncertain. To investigate the cardiotoxicity of transplacentally administered zidovudine (AZT) or AZT plus lamivudine (3TC) in the absence of HIV infection, we evaluated several biomarkers of cardiac mitochondrial structure and cardiac structure and function in a B6C3F1 mouse model. In utero exposure to AZT-3TC resulted in ultrastructural pathology, loss of mitochondria, and altered echocardiographic measurements in newborn mice. Cardiac pathology and dysfunction persisted into the adult life of female mice exposed in utero to AZT, as evidenced by significant dose-dependent heart enlargement, clusters of atypical mitochondria and myofibril alterations, significantly increased cytochrome c oxidase activity, and significantly higher numbers of mutations in mitochondrial tRNA genes compared with unexposed controls at 18 to 24 mo of age. These data led to the hypothesis that the long-term pathology of peri-natal exposure to these NRTIs is related to persistent mitochondrial DNA mutations in cardiac tissue; that is, the primary damage during drug treatment is mutational (as opposed to affecting polymerase gamma and/or other mitochondrial elements) and leads over time to delayed, progressive cardiotoxicity.
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PMID:Persistence of mitochondrial toxicity in hearts of female B6C3F1 mice exposed in utero to 3'-azido-3'-deoxythymidine. 1537 30

Although it is well accepted that treatment with nucleoside reverse transcriptase inhibitors (NRTIs) modifies fat metabolism and fat distribution in humans, the mechanisms underlying these modifications are not yet known. The present investigation examines the effects of chronic oral administration of 3'-azido-3'-deoxythymidine (AZT) on the mitochondrial metabolism and the redox status management of rat white adipose tissues originating from two anatomical sites, as well as of the rat liver. Results showed that AZT treatment induced differential effects on the mitochondrial functions depending on the anatomical localisation. Indeed, in inguinal adipose tissue, a significant decrease in the cytochrome c oxidase activity and in the mitochondrial DNA (mtDNA) content was observed, whereas the activity of citrate synthase, a mitochondrial protein exclusively encoded by the nucleus, was not affected. In contrast, no significant change in these parameters could be detected for epididymal tissue and for liver. In parallel, no oxidative stress could be detected after treatment, for both white adipose tissues and for liver, even though treated liver exhibited several modifications in redox management. Taken together, these data demonstrate differential mitochondrial effects of AZT on subcutaneous versus visceral white adipose tissue. Moreover, the decrease in mitochondrial oxidative capacity of inguinal adipocyte consecutive to AZT treatment is not primarily due to an oxidative stress per se, but rather to a depletion of the mtDNA content per cell.
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PMID:Site specific alterations of adipose tissue mitochondria in 3'-azido-3'-deoxythymidine (AZT)-treated rats: an early stage in lipodystrophy? 1589 94

A metabolic engineering approach was exploited to improve growth and protein secretion in the non-conventional yeast, Schwanniomyces occidentalis. Vitreoscilla hemoglobin (VHb) gene was expressed in S. occidentalis under the control of the native alpha-amylase (AMY1) promoter. Expression of VHb was confirmed by reverse transcriptase polymerase chain reaction and Western blot hybridization analysis. Effect of VHb on growth and protein secretion was studied in synthetic medium under both limiting and non-limiting dissolved oxygen conditions. Under both conditions, VHb-expressing cells exhibited higher oxygen uptake and higher specific growth rates. Levels of extracellular alpha-amylase were also elevated in the VHb-transformed strain relative to the control strain. In amylase production medium, VHb-expressing cells showed 3-fold elevated levels of alpha-amylase and a 31% increase in the total secreted protein under oxygen-limiting environment. VHb was found to localize in the mitochondria in addition to its cytoplasmic location. Inhibition of respiration by antimycin A resulted in the loss of the growth-enhancing effects of VHb. A 2.5-fold increase in the cytochrome c oxidase (COX) activity was observed in VHb-expressing cells relative to the control. In addition to this, exogenously added VHb in the assay mixture augmented COX activity.
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PMID:Expression of Vitreoscilla hemoglobin enhances growth and levels of alpha-amylase in Schwanniomyces occidentalis. 1664 33

In spite of opposing changes in rates of adenosine triphosphate turnover, hypertrophy and atrophy of the heart are accompanied by the same changes in gene expression, resembling a fetal genotype. Fetal hearts are characterized by increased ischemia tolerance. We assessed respiratory capacity of mitochondrial subpopulations from unloaded and pressure-overloaded hearts before and after 15 minutes of normothermic ischemia. Unloading was achieved by heterotopic rat heart transplantation and overloading by aortic banding. Respiratory chain gene expression (NADH dehydrogenase, cytochrome c oxidase [COX]) were analyzed by reverse transcriptase-polymerase chain reaction. Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated by differential centrifugation. Citrate synthase was used as mitochondrial marker enzyme. Adenosine diphosphate-stimulated oxygen consumption (state 3) was measured with a Clark-type electrode. Unloading resulted in atrophy, overloading in hypertrophy. State 3 was reduced in atrophied hearts both in SSM and IFM (SSM: 204 +/- 79 vs 804 +/- 147 natoms oxygen min(-1) mL(-1), P < .001; IFM: 468 +/- 158 vs 1141 +/- 296 natoms oxygen min(-1) mL(-1), P < .05), but was unchanged in hypertrophied hearts. NADH dehydrogenase and COX expression was also decreased with atrophy and was unchanged with hypertrophy. Ischemia caused decreased recovery of citrate synthase in isolates of SSM (P < .05) but not of IFM. State 3 in control hearts was reduced in IFM (-41%, P < .01) and SSM (-19%, not significant). This ischemia-induced decrease was less pronounced in SSM (-2%) and IFM (-22%) of atrophied and IFM (-23%) of hypertrophied hearts. Subsarcolemmal mitochondria of hypertrophied hearts displayed the greatest ischemia-induced decrease of state 3 (-32%, P < .05). In conclusion, (1) long-term changes in workload differentially affect maximal respiratory capacity and ischemia tolerance of isolated mitochondria. The changes are not parallel to the changes in energy requirements. (2) Mitochondria of atrophied hearts appear to be more resistant against ischemia than controls.
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PMID:Differential changes in respiratory capacity and ischemia tolerance of isolated mitochondria from atrophied and hypertrophied hearts. 1683 47


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