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)

The effect of the association of gossypol and Lonidamine on the electron transport in Ehrlich ascites tumor mitochondria has been investigated by addition of drugs to isolated mitochondria. The results may be summarized as follows. (1) Low concentrations of gossypol increase the rate of oxygen consumption at the level of three energy-conserving sites of the respiratory chain. Higher concentrations result in an inhibition of oxygen consumption at (or near) both energy-conserving sites 1 and 2, while energy-conserving site 3 is unaffected. (2) Gossypol, at concentrations at which it exerts its uncoupling effect, stimulates ATPase activity. Higher concentrations inhibit the enzyme activity. (3) The addition of gossypol to mitochondria respiring on pyruvate plus malate or succinate induces a more oxidized state of NAD+ and cytochrome b, respectively. (4) Gossypol enhances the effect of Lonidamine on oxygen consumption. Lonidamine does not affect state 4 respiration, but in the presence of gossypol, it determines a marked decrease in the rate of oxygen consumption. The inhibition of oxidation of NAD-linked substrates is greater than that of FAD-linked substrates. (5) It may be concluded that gossypol is very effective in potentiating the effect of Lonidamine. Moreover, it may be suggested that the antitumor activity of Lonidamine is enhanced if it is used in combination with other drugs and/or treatments, such as hyperthermia, which modify the energy status of mitochondria.
Exp Mol Pathol 1984 Apr
PMID:The effect of gossypol and Lonidamine on electron transport in Ehrlich ascites tumor mitochondria. 670 94

Monoamine oxidase (MAO) depends on a covalently attached FAD cofactor for activity. Activity is depressed in mouse neuroblastoma cells (N1E-115) grown in synthetic N2 medium lacking riboflavin. MAO activity in depleted cells is stimulated by added riboflavin, and this recovery is blocked by inhibitors of RNA and protein synthesis, and not by an inhibitor of protein glycosylation Recovery from riboflavin depletion appears to depend upon new RNA and protein synthesis, and not on the addition of FAD cofactor to an inactive MAO precursor.
Cell Mol Neurobiol 1981 Dec
PMID:Effect of riboflavin on monoamine oxidase activity in cultured neuroblastoma cells. 676 37

The total -SH content of purified NADPH-cytochrome P-450 reductase (NADPH: ferricytochrome oxidoreductase, EC 1.6.2.4) from rabbit liver microsomes accessible to an excess equivalent of PCMB was 7.0 +/- 0.3 mol thiol groups/mol protein. The modification of four -SH groups at low concentration of PCMB stimulated the activity of the enzyme. On the other hand, further blocking of -SH groups (6-7 mol -SH groups/Mol protein) with an excess amount of PCMB completely inhibited cytochrome c (or DCPI) reductase activity. The fluorescence quenching of the flavin was rapidly removed by binding of PCMB to a fifth and sixth -SH group during a gradual titration. Kinetic and fluorimetric analyses confirmed the suggestion that these two -SH groups essential for catalytic function were partly protected by NADP+ or 2'-AMP against the reaction with PCMB. Excess PCMB begins to compete with the ligand preincubated with the enzyme. The spectral perturbation on the addition of approx. 6-7 equiv. PCMB/mol enzyme is accompanied by a slight blue shift of the absorbance maximum at 380 nm, with the appearance of a pronounced shoulder at 475 nm. In contrast to the native enzyme, 3-electron-reduced semiquinone form of PCMB-treated enzyme showed the same absorption spectrum as 1-electron-reduced semiquinone which has an absorption maximum at 585 nm with a broad shoulder around 635 nm. An inhibitory effect may be attributable to the fact that NADPH is less accessible to the FAD binding site as well as the pyridine nucleotide binding site, since the rate of FAD reduction becomes extremely slow after complete modification.
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PMID:Location of functional -SH groups in NADPH-cytochrome P-450 reductase from rabbit liver microsomes. 679 74

The chain fold of the FAD-binding domain of p-hydroxybenzoate hydroxylase resembles the chain folds of the two nucleotide-binding domains of glutathione reductase. This fold consists of a four-stranded parallel beta-sheet sandwiched between a three-stranded antiparallel beta-sheet and alpha-helices. The nucleotides bind in similar positions relative to this chain fold. The best superposition of the folds has been established and geometrically quantified, giving rise to an equivalencing scheme for 110 residue positions, of which only four residues are identical in all three domains. It is discussed whether this chain fold is also present in a number of other FAD-binding proteins with known sequence. After the second strand of the parallel beta-sheet both FAD-binding domains contain long chain excursions, which make intimate contacts to rather distant parts of the respective molecules. In the environment of the isoalloxazine rings we observe interesting similarities. In both enzymes the si-face of this ring is covered by polypeptide, and only the re-face is accessible for the cofactor NADPH. Furthermore, there is a long alpha-helix in each enzyme, which points with its N-terminal start to the O-2 alpha region of isoalloxazine. These helices are spatially in the same position with respect to the isoalloxazine ring but are at quite different positions along the polypeptide chain. Since they can stabilize a negative charge around O-2 alpha, they may be important for the catalytic processes.
J Mol Biol 1983 Jul 05
PMID:Comparison of the three-dimensional protein and nucleotide structure of the FAD-binding domain of p-hydroxybenzoate hydroxylase with the FAD- as well as NADPH-binding domains of glutathione reductase. 687 63

Norcocaine nitroxide was found to be produced via the one-electron oxidation of N-hydroxynorcocaine by hepatic microsomal enzymes from induced and noninduced rats, hamsters, and mice in the presence of an NADPH-generating system. This reaction was demonstrated to be mediated by cytochrome P-450 as suggested by induction experiments using phenobarbital, which markedly enhanced the production of this nitroxide, and by the inhibition of this monooxygenase by metyrapone, which depressed the formation of this free radical. Unlike other nitroxides, norcocaine nitroxide was rapidly reduced by flavoproteins such as cytochrome P-450 reductase and FAD-monooxygenase, but not cytochrome P-450. We believe that since NADPH is consumed during the futile cycling of N-hydroxynorcocaine/norcocaine nitroxide and since NADPH is an essential cofactor of the glutathione reductase system, diminished reduced nucleotide may lead to depressed levels of cellular glutathione. In this manner, we theorize that cocaine initiates hepatotoxicity.
Mol Pharmacol 1982 Mar
PMID:Norcocaine nitroxide. A potential hepatotoxic metabolite of cocaine. 709 46

Chicken embryos in eggs laid by hens that are genetically unable to deposit riboflavin into their eggs die on or about the 13th day of incubation. We show that these riboflavin-deficient embryos grow normally until the day of death and that their heart rate is normal to within an hour of death. The embryos have symptoms of impaired fatty acid oxidation, including decreased activity of FAD-dependent medium-chain acyl CoA dehydrogenase in liver and heart along with a significant accumulation of intermediates of fatty acid oxidation (C10, C12, and C14 acids). Unlike riboflavin-deficient mammals, the embryos do not accumulate dicarboxylic acids derived from omega-oxidation of fatty acids. Blood glucose is near normal on day 10 but declines to undetectable levels by the time of death. Allantoic fluid from the riboflavin-deficient embryos of 11 days or older contains more lactate than 3-hydroxybutyrate, while in normal embryos the reverse is true. No appreciable amounts of glycine-conjugated acids were found. We conclude that the major and perhaps primary pathological effect of riboflavin deficiency in chicken embryos is the impairment of fatty acid beta-oxidation, and that the subsequent depletion of limited carbohydrate reserves leads to sudden death.
Comp Biochem Physiol B Biochem Mol Biol 1995 Jun
PMID:Riboflavin-deficient chicken embryos: hypoglycemia without dicarboxylic aciduria. 759 88

Purification of indole-3-ethanol (IEt) oxidase was carried out from extracts of the seeds of two bean cultivars. The IEt oxidase from the Labrador cultivar was purified more than 1000-fold and had a molecular weight of about 56 kD. The enzyme reaction required oxygen and produced hydrogen peroxide, was not stimulated by either NADP or FAD, and was inhibited by EDTA and iodoacetate. Physiologically-relevant inhibitors included gibberellic acid, indoleacetic acid and indoleacetaldehyde, through at higher than physiological concentrations. IEt oxidase from the Farden Losa cultivar differed in some properties, but an antiserum prepared against this enzyme detected corresponding proteins from the Labrador and Tendergreen cultivars. In developing Tendergreen bean seeds, the IEt oxidase activity was temporally correlated with IEt levels. Parallel immunochemical measurement of IEt was obscured by non-specific reactions.
Biochem Mol Biol Int 1995 Feb
PMID:Purification, characterization and developmental expression of indole-3-ethanol oxidase from seeds of Phaseolus vulgaris. 766 98

Familial (autosomal dominant) Alzheimer's disease (FAD) is a genetically heterogeneous disorder. Mutations in exons 16 and 17 of the amyloid beta-protein precursor (beta PP) gene currently account for less than 2% of FAD kindreds. No known defect in beta PP quantity, structure, or processing accounts for disease-associated beta-amyloid deposition in the majority of early-onset FAD kindreds. Only two out of a sample of 48 pedigrees (particularly the early onset FAD 4 kindred) contributed noticeably to evidence of linkage at the D21S16/13 and S1/S11 loci in the chromosomal region 21q21 [75]. Many early onset FAD pedigrees (including the FAD 1 and FAD 4 kindreds) show strong evidence of linkage to markers in the chromosome 14q24.3 region. Patients with trisomy 21 (Down's syndrome, DS) virtually always develop a histopathological phenotype indistinguishable from FAD, presumably on the basis of increased beta PP gene dosage and transcription. Whereas no beta PP gene duplication has been found in FAD, other mechanisms that augment beta PP production by effects at the transcriptional level could explain some FAD cases. Here, we report that cultured fibroblasts from affected members of the FAD 1 pedigree show a approximately 1.9 fold increase (P = 0.007) in beta PP mRNA levels compared to unaffected members when the cells are grown under stressed conditions in 0.5% serum. The elevated levels of beta PP mRNA in cells cultured in 0.5% serum also cosegregate with haplotypes in the 14q24.3 region when analyzed by linkage methods (LOD score = 3.26 at theta = 0.001). This is the chromosomal region to which FAD in this family has previously been mapped. As expected, fibroblasts from patients with DS used as a control show a similar beta PP mRNA increase. Fibroblasts from the FAD 4 pedigree did not show this defect under the conditions utilized here. beta PP and A beta protein levels were determined quantitatively after metabolic labeling and immunoprecipitation and found to increase 2.0 and 2.5 fold, respectively, in the fibroblasts from affected FAD 1 members. Finally, transient transfections of a beta PP promoter/chloramphenicol acetyl transferase reporter gene construct demonstrated a approximately 3-4 fold increase in beta PP promoter activity in affected fibroblasts from the FAD 1 but not the FAD 4 pedigree. Taken together, these data raise the possibility that an increase in beta PP transcription may underlie the AD phenotype in at least some of the chromosome 14-linked FAD families.
Brain Res Mol Brain Res 1995 Feb
PMID:Beta APP mRNA transcription is increased in cultured fibroblasts from the familial Alzheimer's disease-1 family. 772 30

Form A of two previously described human monoclonal anti-riboflavin IgGs, the GAR [Farhangi, M. & Osserman, E. F. (1976) N. Engl. J. Med. 294, 177-183] and DOT [Merlini, G., Bruening, R., Kyle, R. & Osserman, E. F. (1990) Mol. Immunol. 27, 385-394], has been characterized in terms of binding properties and primary structure. Both forms were isolated as immunocomplexes with bound riboflavin and gave a reconstitutable apoprotein. The riboflavin-reconstituted IgGs showed a similar visible absorption spectrum, with a marked resolution of the 445-nm band and a ratio 445-nm/370-nm peaks of 1.13 for DOT and 1.19 for GAR. Both proteins bind riboflavin, FMN and FAD with a molar ratio ligand/protein of 2:1. DOT and GAR share a very similar affinity for the flavinic ligands; the Kd values for riboflavin and FMN are in the range 1 nM; that for FAD is an order of magnitude higher. DOT and GAR do not form an adduct between the nucleophilic group sulfite and the N(5) position of the flavin, and do not stabilize any flavinic semiquinone during reduction with the xantine/xantine oxidase benzylviologen system. The primary structure of fragment antigen binding (Fab) DOT and heavy-chain variable region (VH) GAR determined in the present study and that already known for the light-chain variable region (VL) GAR [Kiefer, C. R., McGuire, B. S., Osserman, E. F. & Garver, F. A. (1983) J. Immunol. 131, 1871-1875] evidenced that the two IgGs are assembled with VL and VH chains of different subgroups; a lambda III/HIII pair in GAR, and a lambda II/HI pair in DOT. Although less similar each other than to the counterparts of the same subclasses, DOT and GAR share an exclusive identity in the VH CDR3 region.
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PMID:Characterization of the two unique human anti-flavin monoclonal immunoglobulins. 773 90

The gene encoding the flavin-containing monoamine oxidase (MAO-N) of the filamentous fungus Aspergillus niger was cloned. MAO-N is the first nonvertebrate monoamine oxidase described to date. Three partial cDNA clones, isolated from an expression library, were used to identify and clone the structural gene (maoN) from an A. niger genomic DNA library. The maoN gene was sequenced, and analysis revealed an open reading frame that codes for a protein of 495 amino acids with a calculated molecular mass of 55.6 kDa. Sequencing of an internal proteolytic fragment of the purified enzyme confirmed the derived amino acid sequence. Analysis of the deduced amino acid sequence indicates that MAO-N is structurally related to the human monoamine oxidases MAO-A and MAO-B. In particular, the regions known to be involved in the binding of the FAD cofactor show a high degree of homology; however, the conserved cysteine residue to which the flavin cofactor is covalently bound in the mammalian forms is absent in the fungal enzyme. MAO-N has the C-terminal tripeptide Ala-Arg-Leu, which corresponds to the consensus targeting sequence found in many peroxisomal enzymes. The full-length cDNA for MAO-N was expressed in Escherichia coli from the T7 promoter of the expression vector pET3a, yielding a soluble and fully active enzyme form.
Mol Gen Genet 1995 May 20
PMID:Cloning, sequencing and heterologous expression of the monoamine oxidase gene from Aspergillus niger. 777 50


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