Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Measurement of the effect of drugs on the in vivo rates of synthesis of rabbit liver organelle bound proteins were measured following individual treatments with the inducers phenobarbital, 3-methylcholanthrene and PCB (a mixture of polychlorinated biphenyls) and the inhibitors, cycloheximide, aflatoxin B1, chloramphenicol and actinomycin D. Following their isolation from a homogenate containing the combined livers of 14C-leucine injected experimental animals and 3H-leucine injected control animals, purified fractions of the following proteins were prepared: microsomal cytochrome b5, cytochrome P-450, NADH-cytochrome b5 reductase, NADPH-cytochrome P-450 reductase and proteolipids, outer mitochondrial membrane cytochrome b5, NADH-cytochrome b5 reductase and proteolipids, inner mitochondrial membrane cytochrome c, NADH dehydrogenase and proteolipids, intermitochondrial membrane cytochrome b5 and circulating serum albumin. The effect of a drug was examined by measuring the 14C/3H ratio of leucine incorporation of each fraction; ratios which differed markedly from a control value of 1 represented actual changes in the relative rates of protein synthesis. Increased rates of synthesis of cytochrome P-450 and its reductase, intermitochondrial membrane cytochrome b5 and all three proteolipid fractions resulted from each inducer treatment. Treatments with 3-methylcholanthrene and PCB also increased the rate of synthesis of cytochrome b5 and its reductase in both the microsome and outer mitochondrial membrane. In addition, the PCB treatment increased the rates of synthesis of cytochrome c and NADH-dehydrogenase. The rates of synthesis of cytochromes, reductases and of circulating serum albumin were inhibited following treatments with cycloheximide, aflatoxin B1 and actinomycin D. Actinomycin D appeared to inhibit the release of newly synthesized albumin into the bloodstream while chloramphenicol treatment appeared to inhibit the incorporation of cytochrome c into the mitochondria. After 20 hours of treatment with inhibitors, the inhibitory effect of actinomycin D and cycloheximide were still apparent while the rates of protein synt;esis in chloramphenicol and aflatoxin B1 treated animals increased to levels above the controls. The incorporation of radioactively labeled leucine into the proteolipids of the microsomal, and the outer and inner mitochondrial membranes were inhibited following the treatment with actinomycin D and stimulated following the treatment with cycloheximide.
Mol Cell Biochem 1979 Dec 14
PMID:Effect of a single dose of inducers and inhibitors on the rate of synthesis of cytochromes and reductases in liver organelles. 11 59

The phospholipid requirement of membrane-bound enzymes may depend on several reasons. In our laboratory we have investigated lipids (1) as a bidimensional medium required for the movement of Coenzyme Q, a lipid-soluble cofactor of the mitochondrial respiratory chain, and (2) as a hydrophobic environment necessary to impose the proper conformation to membrane-bound enzymic proteins. We have found that Coenzyme Q, once reduced by NADH dehydrogenase, must cross the inner mitochondrial membrane; only quinones having long isoprenoid side chains can easily cross phospholipid bilayers, and this is the reason why a short chain quinone such as CoQ-3 inhibits NADH oxidation. The incapability of short quinones to cross lipid bilayers is due to their disposition in the lipid bilayer, stacked within the phospholipids. The conformational role of lipids has been investigated indirectly observing the kinetics of membrane-bound enzymes, e.g. the mitochondrial ATPase, and directly by circular dichroism. Lipid removal or lipid perturbation with organic solvents induce a decrease of alpha-helical content in mitochondrial proteins, and give rise to a series of kinetic changes in ATPase, including uncompetitive inhibition, increased activation energy, and loss of cooperativity in oligomycin inhibition. The recognition of a conformational role of lipids has allowed us to postulate a working hypothesis for the mechanism of action of general anesthetics. Such drugs have been found by us, by means of spin labels and fluorescent probes, to disrupt lipid protein interactions in several membranes, including synaptic membranes. The loosening of such interactions is believed to induce conformational changes, which will alter ion transport systems necessary to the propagation of neural impulses. Conformational changes induced by anesthetics have been found by us both directly by circular dichroism and indirectly by enzyme kinetics. The conformational effect of anesthetics is not directly exerted on the proteins but is mediated through the lipids. In agreement with this hypothesis we have found that membrane-bound acetylcholinesterase is inhibited by anesthetics, whereas the solubilized enzyme is not inhibited. However, binding of the solubilized enzyme to phospholipids restores anesthetic inhibition.
Mol Cell Biochem 1978 Nov 30
PMID:Biophysical studies on agents affecting the state of membrane lipids: biochemical and pharmacological implications. 15 58

By the use of a mutation, hxB-20, that eliminates purine hydroxylase II activity but retains cross-reacting material and an ancillary NADH dehydrogenase activity, it has been established that 6-hydroxynicotinic acid rather than nicotinic acid, is the true inducer of purine hydroxylase II.
Mol Gen Genet 1979 Jul 02
PMID:Product induction of purine hydroxylase II in Asperigillus nidulans. 38 57

RNA editing of several mitochondrial transcripts in Trypanosoma brucei is developmentally regulated. The cytochrome b and cytochrome oxidase II mRNAs are edited in procyclic-form parasites but are primarily unedited in bloodstream forms. The latter forms lack the mitochondrial respiratory system present in procyclic forms. Editing of the NADH dehydrogenase 7 (ND7) and ND8 transcripts is also developmentally regulated but occurs preferentially in bloodstream forms. Other transcripts, cytochrome oxidase III and ATPase 6, are edited in both life forms. We have identified many minicircle-encoded guide RNAs (gRNAs) for ATPase 6, ND7, and ND8. The characteristics of these gRNAs reveal how extensively edited RNA can be edited in the 3'-to-5' direction. Northern (RNA) blot and primer extension analyses indicate that gRNAs for transcripts whose editing is developmentally regulated are present in both procyclic and bloodstream form parasites. These results suggest that the developmental regulation of editing in these transcripts is not controlled by the presence or absence of gRNAs.
Mol Cell Biol 1992 May
PMID:Guide RNAs for transcripts with developmentally regulated RNA editing are present in both life cycle stages of Trypanosoma brucei. 137 4

The maxicircle of Trypanosoma brucei encodes components of the mitochondrial oxidative phosphorylation system, as do other mitochondrial DNAs, but maxicircle gene identification is complicated by extensive editing of some transcripts. We found that transcripts from the CR1 region were extensively edited, as are other transcripts from maxicircle regions which exhibit strong G versus C strand bias. Editing added 259 uridines and removed 46 uridines to produce an approximately 574-nucleotide mature mRNA. Partially edited cDNAs and potential guide RNAs were also characterized. Initiation and termination codons were created, and they defined an open reading frame encoding a predicted protein of 145 amino acids. This protein contains two iron-sulfur cysteine motifs and is homologous to a subunit of NADH dehydrogenase and to other electron-carrier proteins. Higher levels of both edited and unedited CR1 transcripts accumulated in bloodstream forms of the parasite than in procyclic forms, suggesting developmental regulation of CR1 gene expression.
Mol Cell Biol 1992 May
PMID:Maxicircle CR1 transcripts of Trypanosoma brucei are edited and developmentally regulated and encode a putative iron-sulfur protein homologous to an NADH dehydrogenase subunit. 137 7

NADH:ubiquinone oxidoreductase, the respiratory chain complex I of mitochondria, is an assembly of some 25 nuclear-encoded and 7 mitochondrially encoded subunits. The complex has an overall L-shaped structure formed by a peripheral arm and an elongated membrane arm. The peripheral arm containing one FMN and at least three iron-sulphur clusters constitutes the NADH dehydrogenase segment of the electron pathway. The membrane arm with at least one iron-sulphur cluster constitutes the ubiquinone reducing segment. We are studying the assembly of the complex in Neurospora crassa. By disrupting the gene of a nuclear-encoded subunit of the membrane arm a mutant was generated that cannot form complex I. The mutant rather pre-assembles the peripheral arm with all redox groups and the ability to catalyse NADH oxidation by artificial electron acceptors. The final assembly of the membrane arm is blocked in the mutant leading to accumulation of complementary assembly intermediates. One intermediate is associated with a protein that is not present in the fully assembled complex I. The results demonstrate that the two arms of complex I are assembled independently on separate pathways, and gave a first insight into the assembly pathway of the membrane arm. It is also shown for the first time that the obligate aerobic fungus N. crassa can grow and respire without an intact complex I. Gene replacement in this fungus is therefore a tool for investigation of this complex.
J Mol Biol 1992 Oct 20
PMID:Characterization of assembly intermediates of NADH:ubiquinone oxidoreductase (complex I) accumulated in Neurospora mitochondria by gene disruption. 143 84

The plastid DNA of higher plants contains eleven reading frames that are homologous to subunits of the mitochondrial NADH-ubiquinone oxidoreductase (complex I). The genes are expressed, but a plastid NAD(P)H dehydrogenase has not yet been isolated and the function of the enzyme in plastid metabolism is unknown. Cyanobacteria also contain a NADH dehydrogenase that is homologous to the mitochondrial complex I. The enzyme is sensitive to rotenone and is located on the cytoplasmic and the thylakoid membrane. We report here the sequence of five subunits (ndhA, -I, G, -E and -D) of the NADH dehydrogenase from the unicellular cyanobacterium Synechocystis sp. PCC6803. As in plastid DNA, the genes ndh(A-I-G-E) are clustered and probably constitute an operon. The ndhD gene is associated with a gene encoding an iron-sulphur protein of photosystem I (psaC) as in plastid DNA. In contrast to the situation in plastids, psaC and ndhD are not cotranscribed but transcribed from opposite strands. The deduced amino acid sequence of the cyanobacterial polypeptides is more similar to the corresponding plastid (40-68% identity) than to the corresponding mitochondrial subunits (17-39% identity). Thus, the cyanobacterial NADH-dehydrogenase provides a prokaryotic model system which is more suitable to genetic analysis than the enzyme of plastids.
Plant Mol Biol 1992 Dec
PMID:Cloning and transcription analysis of the ndh(A-I-G-E) gene cluster and the ndhD gene of the cyanobacterium Synechocystis sp. PCC6803. 146 44

In the Arabidopsis thaliana mitochondrial genome the gene coding for subunit 4L of NADH dehydrogenase (nad4L) is located between exon c of the nad5 open reading frame and orf25. The physical proximity of these genes further supports the trans-splicing model for assembly of the nad5 mRNA. Some transcripts comprise the nad4L open reading frame cotranscribed with nad5 exon c and orf25, while other mRNAs contain only nad4L and orf25. Both open reading frames for nad4L and orf25 are edited in several positions with different frequencies.
Mol Gen Genet 1992 Dec
PMID:The nad4L gene is encoded between exon c of nad5 and orf25 in the Arabidopsis mitochondrial genome. 149 48

Intermediate and short stumpy bloodstream forms of Trypanosoma brucei brucei are transitional stages in the differentiation of mammal-infective long slender bloodstream forms into the procyclic forms found in the midgut of the tsetse vector. Although the mitochondria of the proliferative long slender forms do not accumulate rhodamine 123, the mitochondria of the transitional forms attain this ability thus revealing the development of an electromotive force (EMF) across the inner mitochondrial membrane. The EMF is inhibited by 2,4-dinitrophenol, rotenone and salicylhydroxamic acid but not by antimycin A or cyanide. Consequently, NADH dehydrogenase, site I of oxidative phosphorylation, is the source of the EMF and the plant-like trypanosome alternative oxidase (TAO) supports the electron flow serving as the terminal oxidase of the chain. Although the TAO is present in the long slender forms as well, it serves only as the terminal oxidase for electrons from glycerol-3-phosphate dehydrogenase. The data presented here, combined with older data, lead to the conclusion that the mitochondria of transitional intermediate and short stumpy forms likely produce ATP. This putative production is either by F1F0 ATPase driven by the complex I proton pump or by mitochondrial substrate level phosphorylation, or most likely by both. These conclusions contrast with the previously held dogma that all bloodstream form mitochondria are incapable of ATP production.
Mol Biochem Parasitol 1991 Apr
PMID:Mitochondrial development in Trypanosoma brucei brucei transitional bloodstream forms. 164 58

A 6.8 kilobase fragment of mitochondrial DNA from Pneumocystis carinii encodes for apocytochrome b, NADH dehydrogenase subunits 1, 2, 3, and 6, cytochrome oxidase subunit II, and the small subunit of ribosomal RNA. Comparative sequence analysis with a series of organisms representative of the fungal and protozoan groups shows that P. carinii has, consistently, an average similarity of 60% with the fungi but only 20% with the protozoa. The data indicate homology with the fungi for this opportunistic pathogen.
Mol Microbiol 1991 Jun
PMID:Mitochondrial gene sequences show fungal homology for Pneumocystis carinii. 166 5


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