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: KEGG:D02011 (FAD)
5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The DNA sequence of the Salmonella typhimurium ahp locus was determined. The locus was found to contain two genes that encode the two proteins (C22 and F52a) that comprise the S. typhimurium alkyl hydroperoxide reductase activity. The predicted sequence of the F52a protein component of the alkyl hydroperoxide reductase was found to be highly homologous to the Escherichia coli thioredoxin reductase protein (34% identity with many conservative substitutions). The homology was found to be particularly striking in the region containing the redox-active cysteines of the thioredoxin reductase molecule, and among the identities were the redox-active cysteines themselves. Aside from the strong similarity to thioredoxin reductase, overall homology between the F52a protein and other flavoprotein disulfide oxidoreductases such as glutathione reductase, dihydrolipoamide dehydrogenase, and mercuric reductase was found to be rather limited, and the conserved active site segment common to the three proteins was not observed within the F52a protein. However, three short segments that have been implicated in FAD and NAD binding were found to be conserved between the F52a protein and the other disulfide reductases. These results suggest that the alkyl hydroperoxide reductase is the second known member of a class of disulfide oxidoreductases which was represented previously by thioredoxin reductase alone; they also allow the putative assignment of several functional domains.
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PMID:Alkyl hydroperoxide reductase from Salmonella typhimurium. Sequence and homology to thioredoxin reductase and other flavoprotein disulfide oxidoreductases. 219 51

Rats maintained on a tryptophan supplemented diet and exposed to U.V. radiation showed decreased concentration of ascorbic acid in serum. In the lens, a small increase in the urea-mercaptoethanol soluble fraction was observed suggesting some oxidation of P-SH groups. The decreased concentrations of lens glutathione and ascorbic acid were accompanied with increased concentration of malondialdehyde suggesting increased oxidative stress. The activities of glutathione peroxidase decreased by about 40%. Though the activity of glutathione reductase decreased by about 58%, addition of FAD in the enzyme assay system showed restoration of lost activity. Additive effect of raised serum tryptophan concentration and ultraviolet radiation in causing damage to the eye lens is suggested.
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PMID:Effects of a tryptophan supplemented diet and U.V. radiation on the rat lens. 227 28

Steady-state and laser flash photolysis techniques have been used to examine the photoreduction of yeast glutathione reductase by the one-electron reduction products of 5-deazariboflavin and the viologen analogue 1,1'-propylene-2,2'-bipyridyl. Steady-state photoreduction of the enzyme with the viologen generates the two-electron-reduced form, whereas photoreduction with deazaflavin generates the anion semiquinone. Flash photolysis indicates that the product of viologen radical reduction is also a semiquinone, suggesting that this species is rapidly further reduced by viologen in the steady-state experiment to form the EH2 enzyme. This reduction is apparently inhibited when deazaflavin is the photoreductant, perhaps due to complexation of the anion semiquinone with deazaflavin. Steady-state experiments demonstrate that complexation of the anion semiquinone with NADP+ also inhibits further reduction. Both one-electron reduction reactions of oxidized glutathione reductase proceed at close to diffusion-controlled rates (second-order rate constants = 10(8)-10(9) M-1 s-1), despite the relatively buried nature of the FAD cofactor. Addition of NADP+ and oxidized glutathione produced no effects on the kinetics of the initial entry of the electron into the enzyme. No kinetic evidence of intramolecular electron transfer involving the FAD and the protein disulfide was obtained during or subsequent to the initial one-electron reduction process. Thus, if this reaction occurs in the semiquinone, it must be quite rapid (k greater than 8000 s-1).
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PMID:Steady-state and laser flash induced photoreduction of yeast glutathione reductase by 5-deazariboflavin and by a viologen analogue: stabilization of flavin adenine dinucleotide semiquinone species by complexation. 238 72

10-(4'-Chlorophenyl)-3-methylflavin has antimalarial activity in vitro and in vivo (Cowden et al., J Med Chem 31: 799, 1988). This flavin analog and two of its derivatives were found to inhibit the antioxidant flavoenzyme glutathione reductase from human erythrocytes in its isolated form as well as in hemolysates. The mixed-type inhibition was completely reversible, the Ki-values being of the order of 1 microM. Surprisingly, the drugs were not competitive with FAD, but with GSSG, one of the enzyme's substrates. Malaria parasite glutathione reductase, extracted from Plasmodium falciparum, could also be inhibited by the compounds. Studies on the effects of the substances on P. falciparum in vitro, which were demonstrated morphologically and by growth inhibition, confirmed previous observations with 10-(4'-chlorophenyl)-3-methylflavin and showed similar parasiticidal characteristics for the two new derivatives. The activities of five other erythrocytic enzymes tested were not impaired by the drugs, nor was the nucleotide metabolism of erythrocytes and/or parasites significantly changed. Permeation into red blood cells was demonstrated for one compound by 19F-NMR-spectroscopy. Inhibition of glutathione reductase might contribute to, or account for, the antimalarial activity of this group of flavin analogs.
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PMID:Flavin analogs with antimalarial activity as glutathione reductase inhibitors. 240 94

Bacterial plasmids have genes that confer highly specific resistances to As, Bi, Cd, Cu, Cr, Hg, Pb, Te, Zn, and other toxic heavy metals. For each toxic cation or anion, generally a different resistance system exists, and these systems may be "linked" together on multiple resistance plasmids. For Cd2+, AsO2-, AsO4(3)-, Hg2+, and organomercurials, DNA sequence analysis has supplemented direct physiological and biochemical experiments to produce sophisticated understanding. The cadA ATPase of S. aureus plasmids is a 727 amino acid membrane ATPase that pumps Cd2+ from the cells as rapidly as it is accumulated. This polypeptide is related by sequence to other cation translocating ATPases, including the membrane K+ ATPases of Escherichia coli and Streptococcus faecalis, the H+ ATPases of yeast and Neurospora, the Na+/K+ ATPases of vertebrate animals, and the Ca2+ ATPases of rabbit muscle. The conserved residues include the aspartyl residue that is phosphorylated, the lysine involved in ATP binding, and the proline within a membrane translocating region. The arsenate and arsenite translocating ATPase consists of 3 polypeptides (from DNA sequence analysis), including a recognizable ATP binding protein (arsA), an integral membrane protein (arsB gene), and a substrate specificity subunit (arsC gene). Inorganic mercury and organomercurial degradation is carried out by a series of about 6 polypeptides, including 2 soluble intracellular enzymes (organomercurial lyase and mercuric reductase). The latter is related by sequence and function to glutathione reductase and lipoamide dehydrogenase of prokaryotes and eukaryotes. These enzymes are dimeric, FAD-containing, NAD(P)H-dependent oxidoreductases. Other recognizable polypeptides in the mer system include a DNA-binding regulatory protein from the merR gene and a Hg2+ transport system consisting of a periplasmic Hg2(+)-binding protein (merP gene) and a membrane protein (merT gene) in gram negative systems.
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PMID:DNA sequence analysis of bacterial toxic heavy metal resistances. 248 81

Mitomycin-C (MT-C) inhibits human erythrocyte glutathione reductase (EGR). We found that Km values of EGR for GSSG, NADPH, and FAD were 1.3 X 10(-4) mol/l, 2.3 X 10(-5) mol/l, and 3.9 X 10(-7) mol/l respectively, and that EGR was inhibited by MT-C non-competitively with respect to both the substrate GSSG (Ki = 4.8 X 10(-5) mol/l) and the cofactor NADPH (Ki = 2.2 X 10(-4) mol/l), and competitively with respect to FAD (Ki = 4.2 X 10(-5) mol/l). On the other hand, we demonstrated that FAD makes a complex with MT-C, the dissociation constant (K = 6.5 X 10(-5) mol/l) of which was obtained from fluorescence quenching of FAD with MT-C. It also became clear that spectra wf FAD at around 375 nm changes with increasing MT-C concentration. So, the data strongly suggest that the mechanism of inhibition of EGR by MT-C is mainly due to complex formation of the co-enzyme FAD with MT-C.
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PMID:Mechanism of inhibition of erythrocyte glutathione reductase by mitomycin-C. 249 19

Using synchrotron radiation, the X-ray diffraction intensities of crystals of p-hydroxy-benzoate hydroxylase, complexed with the substrate p-hydroxybenzoate, were measured to a resolution of 1.9 A. Restrained least-squares refinement alternated with rebuilding in electron density maps yielded an atom model of the enzyme-substrate complex with a crystallographic R-factor of 15.6% for 31,148 reflections between 6.0 and 1.9 A. A total of 330 solvent molecules was located. In the final model, only three residues have deviating phi-psi angle combinations. One of them, the active site residue Arg44, has a well-defined electron density and may be strained to adopt this conformation for efficient catalysis. The mode of binding of FAD is distinctly different for the different components of the coenzyme. The adenine ring is engaged in three water-mediated hydrogen bonds with the protein, while making only one direct hydrogen bond with the enzyme. The pyrophosphate moiety makes five water-mediated versus three direct hydrogen bonds. The ribityl and ribose moieties make only direct hydrogen bonds, in all cases, except one, with side-chain atoms. The isoalloxazine ring also makes only direct hydrogen bonds, but virtually only with main-chain atoms. The conformation of FAD in p-hydroxybenzoate hydroxylase is strikingly similar to that in glutathione reductase, while the riboflavin-binding parts of these two enzymes have no structural similarity at all. The refined 1.9 A structure of the p-hydroxybenzoate hydroxylase-substrate complex was the basis of further refinement of the 2.3 A structure of the enzyme-product complex. The result was a final R-factor of 16.7% for 14,339 reflections between 6.0 and 2.3 A and an improved geometry. Comparison between the complexes indicated only small differences in the active site region, where the product molecule is rotated by 14 degrees compared with the substrate in the enzyme-substrate complex. During the refinements of the enzyme-substrate and enzyme-product complexes, the flavin ring was allowed to bend or twist by imposing planarity restraints on the benzene and pyrimidine ring, but not on the flavin ring as a whole. The observed angle between the benzene ring and the pyrimidine ring was 10 degrees for the enzyme-substrate complex and 19 degrees for the enzyme-product complex. Because of the high temperature factors of the flavin ring in the enzyme-product complex, the latter value should be treated with caution. Six out of eight peptide residues near the flavin ring are oriented with their nitrogen atom pointing towards the ring.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Crystal structure of the p-hydroxybenzoate hydroxylase-substrate complex refined at 1.9 A resolution. Analysis of the enzyme-substrate and enzyme-product complexes. 255 83

A peroxide reductase (peroxidase) which converts lipid hydroperoxides and other alkyl hydroperoxides to the corresponding alcohols, using either NADH or NADPH as the reducing agent, has been identified in both Salmonella typhimurium and Escherichia coli. This enzyme is shown to play a role in protecting against alkyl hydroperoxide mutagenesis. To our knowledge this work represents the first description of an NAD(P)H peroxidase in enteric bacteria and the first reported bacterial peroxidase to exhibit high activity toward alkyl hydroperoxides. A high performance liquid chromatography-based assay for the alkyl hydroperoxide reductase has been developed by monitoring the reduction of cumene hydroperoxide, a model alkyl hydroperoxide. By using this assay, the enzyme has been purified from a S. typhimurium regulatory mutant, oxyR1, which overexpresses a number of proteins involved in defenses against oxidative damage, and which contains 20-fold more of the alkyl hydroperoxide reductase than the wild-type strain. The purified activity requires the presence of two separable components having subunit molecular weights of 22,000 and 57,000. The 57-kDa protein contains a bound FAD cofactor and can use either NADH or NADPH as an electron donor for the direct reduction of redox dyes, or of alkyl hydroperoxides when combined with the 22-kDa protein. This enzyme may thus serve as a prokaryotic equivalent to the glutathione reductase/glutathione peroxidase system in eukaryotes.
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PMID:An alkyl hydroperoxide reductase from Salmonella typhimurium involved in the defense of DNA against oxidative damage. Purification and properties. 264

Yeast glutathione reductase (E.C. 1.6.4.2) catalyzes the oxidation of NADPH by p-quinones and ferricyanide with a maximal turnover number (TNmax) of 4-5 s-1.NADP+ stimulates the reaction and the TNmax/Km value of acceptors is reached at NADP+/NADPH greater than or equal to 100. TNmax is increased up to 30-33 s-1. The stimulatory effect of NADP+ may be associated with its complexation with the NADPH-binding site in the reduced enzyme (Kd = 40-60 microM). It is suggested that NADP+ shifts the electron density towards FAD in the two-electron-reduced enzyme and, evidently, changes its one-electron-reduction potentials, while quinones oxidize an equilibrium form of glutathione reductase containing reduced FAD. In the absence of NADP+ the reduction of quinones by glutathione reductase proceeds mainly in a two-electron manner. At NADP+/NADPH = 100 a one-electron reduction makes up 44% of the total process. At pH 6.0-7.0 the reduced forms of naphthoquinones undergo cyclic redox conversions. A hyperbolic dependence exists of the log TN/Km of quinones on their one-electron-reduction potentials.
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PMID:One- and two-electron reduction of quinones by glutathione reductase. 264 41

Glutathione reductase from Escherichia coli is inactivated when incubated with either NADPH or NADH. The process is inversely dependent on the enzyme concentration. Inactivation is rapid and monophasic with 1 microM NADPH and 1 nM enzyme FAD giving a t1/2 of 1 min. Complex formation between NADPH and the two-electron reduced enzyme (EH2) at higher levels of NADPH protects against rapid inactivation. NADP+, produced in a side reaction with oxygen, also protects by forming a complex with EH2. These complexes make analysis of the concentration dependence of the inactivation process difficult. Inactivation with NADH, where complexes do not interfere, is slower but can be analyzed more readily. With 152 microM NADH and 5.4 nM enzyme FAD, the time required for 50% inactivation is 17 min. The process is markedly biphasic, reaching the final inactivation level after 5-7 h. Analysis of the relationship between the final level of inactivation with NADH and the enzyme concentration indicates that inactivation is due to dissociation of the normally dimeric enzyme. Thus, the position of the dimer-monomer equilibrium between an active dimeric two-electron reduced species and an inactive monomeric two-electron reduced form determines the enzyme activity. An apparent equilibrium constant (Kd) for dissociation of dimer obtained from the anaerobic concentration dependent inactivation curves is 220 nM. Enzyme inactivated with NADH can be reactivated with glutathione, and the reactivation kinetics are second order, monomer-monomer over 75% of the reaction with an average apparent association rate constant (ka) of 13.1 (+/- 5.5) X 10(6) M-1 min-1.
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PMID:Inactivation-reactivation of two-electron reduced Escherichia coli glutathione reductase involving a dimer-monomer equilibrium. 266 73


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