Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D02011 (FAD)
 5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The system involved in the reduction of 2-[4'-di(2''-bromopropyl) aminophenylazolbenzoic acid (CB10-252), an agent designed for treating primary liver cell cancer, has been demonstrated to be localised mainly in the 108 000 X g supernatant fraction of rat liver homogenate. It is also present in other organs particularly in the spleen. DAB-azoreductase as shown previously is present almost entirely in the microsomal fraction and is found in high concentration only in liver. The pH maximum for CB10-252-azoreductase implying the importance of the 2'-carboxyl group in determining substrate specificity. The use of enzyme inhibitors and other additives showed that CB10-252 WAS NOT AXANTHINE OXIDASE OR DIHYDROFOLATE REDUCTASE. Its activity was not affected by carbon monoxide, phenobarbitone (PB), or 3-methylcholanthrene (MC) pretreatment. Enhancement of the activity by ferrous ions and FAD indicated that at least part of the reduction system could involve a flavoprotein with FAD as the prosthetic group. The activity of CB10-252-azoreductase and methylred-azoreductase was reduced by menadione (vitamin K3), cyanide and propylgallate. A diaphorase preparation from pig heart reduced both CB10-252 and methylred with both NADPH- and NADH-generating systems.
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PMID:Some characteristics of two azoreductase systems in rat liver. Relevance to the activity of 2-[4'-di(2"-bromopropyl)-aminophenylazo]benzoic acid (CB10-252), a compound possessing latent cytotoxic activity. 0 Jan 49

Although dihydropyrimidine dehydrogenase has been purified to varying degrees from several species, very little is known about the human enzyme. The importance of this enzyme has recently been shown with cancer chemotherapy, particularly in patients with genetic deficiency of this enzyme. In the present study, this enzyme was purified 7800-fold to homogeneity from human liver by introducing several novel methods including chromatofocusing, HPLC gel filtration, reversed-phase HPLC for the enzyme assay. Purified human enzyme has a molecular mass of 210 +/- 5 kDa and appears to be composed of two subunits. The apparent pI is pH 4.6 (+/- 0.2). The human enzyme contains approximately four flavin nucleotide molecules (two each of FAD and FMN) and 33 iron atoms per molecule of enzyme. Kinetic studies with uracil, thymine, 5-fluorouracil, and NADPH were carried out. Amino acid composition and the N-terminal amino acid sequence of this enzyme were reported. A rabbit polyclonal antibody was raised and shown to be specific for the human liver enzyme. In conclusion, in the present manuscript, we report not only a novel procedure for purification of dihydropyrimidine dehydrogenase from human liver but also new data on its properties compared to other species, which will provide a basis for further biochemical and molecular studies of this enzyme.
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PMID:Purification and characterization of dihydropyrimidine dehydrogenase from human liver. 151 48

The cytosolic molybdoflavoprotein xanthine oxidase has been shown to catalyze the reduction of exocyclic nitro groups to the corresponding nitroso, hydroxylamino and amino derivatives for a wide variety of xenobiotics including the nitrated polycyclic aromatic hydrocarbons 1-nitropyrene and 3-nitrofluoranthene. Using commercially available bovine liver xanthine oxidase, we have studied the kinetics of the metabolism of 1-nitropyrene and 3-nitrofluoranthene. The nitroreduction of these nitro compounds in the presence of xanthine oxidase is dependent on the presence of hypoxanthine or xanthine and the absence of oxygen. This nitroreduction is independent of added flavins (FMN and FAD), unlike the related molybdoflavoprotein aldehyde oxidase. Xanthine oxidase has a Km of 0.7 microM and Vmax of 0.06 nmol/min per unit enzyme for 1-nitropyrene and a Km of 8.6 microM and Vmax of 0.7 nmol/min per unit enzyme for 3-nitrofluoranthene. The importance of these kinetic constants in evaluating the cytosolic metabolism of 1-nitropyrene and 3-nitrofluoranthene are discussed.
Cancer Lett 1990 Oct 08
PMID:The kinetics of 1-nitropyrene and 3-nitrofluoranthene metabolism using bovine liver xanthine oxidase. 220 87

The flavoprotein DT-diaphorase (EC 1.6.99.2) is believed to play an important role in the body's defense system. This enzyme has been purified 13,000-fold with a recovery of 58% from a cytosolic fraction of abdominal fat obtained from an obese patient undergoing elective surgery. Purification of the enzyme to electrophoretic homogeneity was achieved after two chromatographic steps: (1) affinity chromatography on azodicumarol Sepharose 6B; (2) anion exchange chromatography on DEAE Sephacel. The enzyme exhibits a monomer molecular mass of 32 kDa in SDS-PAGE and has 1 FAD prosthetic group per 32 kDa monomer. The FAD prosthetic group appears to be firmly attached to the apoproprotein. The enzyme reduces azodyes and quinones and demonstrates a broad substrate specificity. The enzyme has characteristics that are similar to DT-diaphorase purified from rodent liver, especially the rat liver enzyme. Estimated Km values for NADH, NADPH and menadione are 200, 140 and 3.3 microM, respectively. Vmax values for these substrates in the same order are 762, 667 and 294 mumol/mg.min. Dicumarol and warfarin exhibited competitive inhibition with pyridine nucleotides. The inhibition constants (Ki) for the drugs were estimated to be 10 nM and 2.2 microM, respectively. When compared to several other tissues, abdominal fat has one of the highest DT-diaphorase activities (Martin, L.F., Patrick, S.D. and Wallin, R. (1987) DT-diaphorase in morbidly obese patients. Cancer Lett., 36, 341-347), but the specific role of the enzyme in human fat is unknown.
Cancer Lett
PMID:Human DT-diaphorase, a potential cancer protecting enzyme. Its purification from abdominal adipose tissue. 246 Feb 16

Riboflavin supply was studied in 164 adult inhabitants of the Kara-Kalpak ASSR where a high incidence of cancer of the esophagus and precancer changes of the esophageal mucosa were recorded. Endoscopy was used to investigate the morphological picture of the esophageal mucosa. A standard method for evaluation of the activation coefficient (AC) of erythrocytic glutathion-reductase (EC1.6.4.2) in the presence of FAD was used as a criterion of the body supply with riboflavin. Pronounced riboflavin deficiency (AC greater than or equal to 1.30) and B2 hypovitaminosis (AC = 1.20-1.29) were observed in 17 and 23% of the cases, respectively. Statistical analysis of the data obtained evidences that insufficient supply with riboflavin is recorded, on an average, 3.5-5.5 times more frequently in subjects with pronounced catarrhal esophagitis, combined with or without leukoplakia, than in the control group of subjects with out pronounced changes in the esophageal mucosa. No positive statistically significant association between low supply of the body with riboflavin and atrophic esophagitis has been established.
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PMID:[Riboflavin supply of the Kara-Kalpak ASSr population with pathologic changes of the esophageal mucosa]. 252

The incorporation of radiolabeled riboflavin into flavin mononucleotide, flavin adenine dinucleotide, and flavin covalently bound to protein was determined in Novikoff hepatoma grown in both riboflavin-deficient and normal chow-fed rats. In Novikoff hepatoma, the incorporation of [14C]riboflavin into covalently bound flavins relative to that into FAD was substantially greater than that in host liver, and the turnover rate of riboflavin was also accelerated in tumor compared with the liver. The magnitude of incorporation of [14C]riboflavin into each of the various flavin fractions was substantially greater in tumors from riboflavin-deficient animals than in tumors from control animals. These data support the hypothesis that in conditions of riboflavin deprivation, Novikoff hepatoma maintains the levels of the physiologically important flavin coenzymes at the expense of the free riboflavin fraction. The incorporation of riboflavin into covalently bound flavins relative to that into FAD is substantially greater in Novikoff hepatoma than in liver. Accordingly, covalently bound flavins are either present in greater amounts or regulated differently in tumor than in normal tissue. Because the flavin moiety cannot be reutilized, the covalently bound flavin fraction in Novikoff hepatoma theoretically should be able to sequester riboflavin and thereby deplete the body reserves of this vitamin when dietary intake is marginal.
Nutr Cancer 1987
PMID:Disturbances in the formation of FAD and covalently bound flavins in Novikoff hepatoma from riboflavin-deficient rats. 361 19

Azelaic acid has been shown to inhibit thioredoxin reductase (TR) at the surface of guinea pig and human skin, on cultures of human keratinocytes, melanocytes, melanoma cells, murine melanoma cells (Cloudman S91), and on purified enzymes from Escherichia coli, rat liver, and human melanoma. Human melanoma cells are more resistant to inhibition by azelaic acid than murine melanoma or human melanocytes. Kinetic studies with pure TRs indicate that azelaic acid is a reversible competitive inhibitor. Fluorescence spectroscopy has been used to show that azelaic acid does not interfere with electron transfer from NADPH to FAD on TR. However, azelaic acid does inhibit electron transfer from the dithiolate active site of this enzyme. Inhibition by azelaic acid is pH-dependent, requiring the dissociation of both carboxylate groups, and also the dissociation of the active site dithiol groups. Binding studies with [14C]azelaic acid at different pHs, indicate that inhibition is first due to the formation of a thioester on the active thiolate groups followed by transacylation of a basic amino acid residue in the active site. A comparative study of TR inhibition by C6, C9, C10 and C12 saturated dicarboxylic acids was also determined on guinea pig skin in vivo. These homologous dicarboxylic acids gave greater inhibition with increasing size (i.e. mol wt.).
Cancer Lett 1987 Sep
PMID:Azelaic acid as a competitive inhibitor of thioredoxin reductase in human melanoma cells. 365 30

Quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2], also called DT diaphorase, is a homodimeric FAD-containing enzyme that catalyzes obligatory NAD(P)H-dependent two-electron reductions of quinones and protects cells against the toxic and neoplastic effects of free radicals and reactive oxygen species arising from one-electron reductions. These two-electron reductions participate in the reductive bioactivation of cancer chemotherapeutic agents such as mitomycin C in tumor cells. Thus, surprisingly, the same enzymatic reaction that protects normal cells activates cytotoxic drugs used in cancer chemotherapy. The 2.1-A crystal structure of rat liver quinone reductase reveals that the folding of a portion of each monomer is similar to that of flavodoxin, a bacterial FMN-containing protein. Two additional portions of the polypeptide chains are involved in dimerization and in formation of the two identical catalytic sites to which both monomers contribute. The crystallographic structures of two FAD-containing enzyme complexes (one containing NADP+, the other containing duroquinone) suggest that direct hydride transfers from NAD(P)H to FAD and from FADH2 to the quinone [which occupies the site vacated by NAD(P)H] provide a simple rationale for the obligatory two-electron reductions involving a ping-pong mechanism.
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PMID:The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction. 756 29

Atypical decubital fibroplasia (FAD) occurs especially in elderly and physically debilited or immobilized patients. We report one observation which is peculiar due to the patient's young age and its circumstances. The painless mass is situated in hyperpressure areas (shoulder, posterior or lateral chest wall, sacrum). The lesion is situated in the deep subcutis and has ill defined limits; it is characterized by zones of fibrinoid necrosis and fibrosis and a prominent myxoid stroma. The differential diagnoses includes mesenchymatous malignant tumors and non neoplastic fibroblastic proliferations such as proliferative fasciitis and decubitus ulcer. The prominent underlying factor and the initial event contributing to its pathogenesis seems to be ischemia. Although some recurrent cases have been reported, FAD is a benign lesion whose treatment is surgical removal.
Bull Cancer 1996 Jan
PMID:[Atypical decubitus fibroplasia: a recent entity. Apropos of a case of an adolescent girl]. 867 61

Fanconi anaemia (FA) is an autosomal recessive disorder characterized by a diversity of clinical symptoms including skeletal abnormalities, progressive bone marrow failure and a marked predisposition to cancer. FA cells exhibit chromosomal instability and hyper-responsiveness to the clastogenic and cytotoxic effects of bifunctional alkylating (cross-linking) agents, such as diepoxybutane (DEB) and mitomycin C (MMC). Five complementation groups (A-E) have been distinguished on the basis of somatic cell hybridization experiments, with group FA-A accounting for over 65% of the cases analysed. A cDNA for the group C gene (FAC) was reported and localized to chromosome 9q22.3 (ref.8). Genetic map positions were recently reported for two more FA genes, FAA (16q24.3) and FAD (3p22-26). Here we report the isolation of a cDNA representing the FAA gene, following an expression cloning method similar to the one used to clone the FAC gene. The 5.5-kb cDNA has an open reading frame of 4,368 nucleotides. In contrast to the 63-kD cytosolic protein encoded by the FAC gene, the predicted FAA protein (M(r) 162, 752) contains two overlapping bipartite nuclear localization signals and a partial leucine zipper consensus, which are suggestive of a nuclear localization.
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PMID:Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. 894 34


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