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)

It was demonstrated in heterozygous alpha 1- and beta-thalassaemia, that the slow rate of red-cell metabolism of vitamin B6, previously shown to be inherited, is regulated by the FMN-dependent pyridoxine (pyridoxamine) phosphate oxidase, as in control subjects. In this study, 60% of the patients with thalassaemia had a low B6 oxidase activity. An inverse correlation with the stimulation of the FAD-dependent glutathione reductase activity by FAD confirmed that red-cell riboflavin status was responsible. The inherited nature and lack of signs of nutritional riboflavin deficiency led to the conclusion that this was the result of a slow rate of red-cell metabolism of riboflavin. Stimulation of glutathione reductase activity by FAD correlated inversely with its basic activity in thalassaemia and control subjects. There was a high incidence of a low activity of this enzyme per red cell in patients with thalassaemia. The possibility that a low activity of glutathione reductase and a slow metabolism of B6 and riboflavin in the red-cell might play a part in the degree of severity of the thalassaemic disease is discussed.
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PMID:Low red cell activity of pyridoxine (pyridoxamine) phosphate oxidase and glutathione reductase associated with thalassaemia. 733 97

The red-cell enzymes, glutathione reductase (FAD-dependent) and pyridoxine (pyridoxamine) phosphate oxidase (FMN-dependent), were studied in control subjects. The wide range in the glutathione reductase activity correlated inversely with the percentage stimulation by FAD added in vitro, and with pyridoxine (pyridoxamine) phosphate oxidase activity. Both enzymes were stimulated after ingestion of riboflavin. The results support the suggestion that the rate of metabolism of riboflavin in the red cell controls the activity of both enzymes, and the rate of red-cell metabolism of vitamin B-6.
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PMID:Glutathione reductase activity and pyridoxine (pyridoxamine) phosphate oxidase activity in the red cell. 741 21

Using methods for database screening with individual protein sequences and alignment blocks, a conserved domain is delineated in a group of proteins including several FAD-dependent oxidases. Two motifs within this domain resemble phosphate-binding loops and may be directly involved in FAD binding. These motifs can be readily distinguished from previously described nucleotide-binding sites using a method for database screening with position-dependent weight matrices derived from alignment blocks. Unexpectedly, this group of known and predicted FAD-dependent oxidases includes the product of the DIMINUTO gene, which is involved in Arabidopsis development, and its homologues from man and Mycobacterium leprae.
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PMID:A putative FAD-binding domain in a distinct group of oxidases including a protein involved in plant development. 754 89

A deficient activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase (m-GDH) in the pancreatic islet B-cell may represent a contributing factor in the pathogenesis of non-insulin-dependent (Type 2) diabetes. This enzyme controls circulation in the glycerol phosphate shuttle and, hence, plays a key role in the B-cell glucose-sensing device. An impaired activity of this enzyme in pancreatic islets was documented in several, but not all, animal models of inherited or acquired non-insulin-dependent diabetes. Enzymatic studies conducted in lymphocytes or islets from diabetic patients, as well as a search for possible mutations of the m-GDH gene, were recently undertaken to extend these observations to human subjects.
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PMID:Non-insulin-dependent diabetes mellitus and islet B-cell mitochondrial glycerophosphate dehydrogenase deficiency. 764 19

In two areas in Italy where malaria was endemic--in the Po delta and Maremma on the west coast--we have found a high prevalence of an inherited flavin-deficient red cell in the normal population, suggesting selection by malaria. This study in Sardinia enabled a direct comparison of red-cell activities of FAD-dependent glutathione reductase (EGR) and FMN-dependent pyridoxine phosphate (PNP) oxidase in an ethnically homogeneous population, between two coastal villages where malaria was endemic from 300 B.C. and two mountain villages with no history of malaria. Both enzyme activities were significantly lower on the coast, and it did not seem that this could be explained by possible small differences in dietary riboflavin. As was thought to be the case in Ferrara and Grosseto, it is probable that a genetically controlled flavin-deficient red cell was selected for by malaria. Low EGR apoenzyme activity was more common on the coast, usually explaining the accompanying low basic EGR activity, and may also have been selected for by malaria. This adds to evidence from others that the mechanism of defence of a flavin-deficient red cell against malaria may be through EGR deficiency. It could also play a part in the protection given by heterozygous beta-thalassemia. The multifactorial protection of the population against malaria is discussed.
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PMID:Deficiency of two red-cell flavin enzymes in a population in Sardinia: was glutathione reductase deficiency specifically selected for by malaria? 766 97

We analyzed the folding, covalent flavinylation, and mitochondrial import of the rabbit reticulocyte lysate-translated bacterial 6-hydroxy-D-nicotine oxidase (6-HDNO) fused to the mitochondrial targeting sequence of rat liver dimethylglycine dehydrogenase. Translation of 6-HDNO in FAD-supplemented reticulocyte lysate resulted in a protein that contained covalently incorporated FAD, exhibited enzyme activity, and was trypsin-resistant, a characteristic of the tight conformation of the holoenzyme. The attached mitochondrial presequence did not prevent folding, binding of FAD, or enzyme activity of the 6-HDNO moiety of the fusion protein (pre-6-HDNO). Pre-6-HDNO was imported into rat liver mitochondria and processed by the mitochondrial processing peptidase. Incubation of the trypsin-resistant pre-holo-6-HDNO protein with deenergized rat liver mitochondria demonstrated that upon contact with mitochondria, the protein was unfolded and became trypsin sensitive. Mitochondrial import assays showed that the unfolded pre-holo-6-HDNO with covalently attached FAD was imported into rat liver mitochondria. Inside the mitochondrion the holo-6-HDNO was refolded into the trypsin-resistant conformation. However, when pre-apo-6-HDNO was imported only part of the protein became trypsin resistant (approximately 20%). Addition of FAD and the allosteric effector glycerol 3-phosphate to apo-6-HDNO containing mitochondrial matrix was required to transform the protein into the trypsin-resistant conformation characteristic of holo-6-HDNO.
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PMID:Folding, flavinylation, and mitochondrial import of 6-hydroxy-D-nicotine oxidase fused to the presequence of rat dimethylglycine dehydrogenase. 771 2

The Escherichia coli MurB gene encoding UDP-N-acetylenolpyruvylglucosamine reductase was expressed to a level of approximately 100 mg/L as a fusion construct with maltose binding protein. Rapid affinity purification, proteolysis, and anion exchange chromatography yielded homogeneous enzyme containing 1 mol/mol bound FAD. Enzyme was maximally activated by K+, NH4+, and Rb+ at cation concentrations between 10 and 50 mM. Steady-state enzyme kinetics at pH 8.0 and 37 degrees C revealed weak and strong substrate inhibition by NADPH and UDP-N-acetylenolpyruvylglucosamine, respectively, where the KiS were 910 microM and 73 microM. Substrate inhibition was pH dependent for both substrates. Initial velocity measurements as a function of both substrates produced patterns consistent with a ping pong bi bi double competitive substrate inhibition mechanism. Data at pH 8.0 yielded kinetic constants corresponding to Km,UNAGEP = 24 +/- 3 microM, Ki,UNAGEP = 73 +/- 19 microM, Km,NADPH = 17 +/- 3 microM, Ki,NADPH = 910 +/- 670 microM, and kcat = 62 +/- 3 s-1. A slow anaerobic exchange reaction with thio-NADP+ provided evidence for release of NADP+ in the absence of UNAGEP. Alternate reduced nicotinamide dinucleotides, including NHXDPH, 3'-NADPH, and alpha-NADPH, were substrates, whereas NADH was not. Several nucleotides, including ADP and UDP, were weak inhibitors of the enzyme with inhibition constants between 5 and 97 mM. Various analogs of NADP+, including 3'-NADP+, thio-NADP+, APADP+, NEthDP+, and NHXDP+, were inhibitors of the enzyme with respect to NADPH and yielded inhibition constants in the range of 110-1100 microM. Analogs without the 2'- or 3'-phosphate of NADPH or NADP+ were not substrates or inhibitors. Double inhibition experiments with varied APADP+ and UNAG produced inhibition patterns consistent with mutually exclusive inhibitor binding. The data suggest that NADPH and UNAGEP share a subsite that prevents both molecules from binding at once.
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PMID:Steady-state kinetic mechanism of Escherichia coli UDP-N-acetylenolpyruvylglucosamine reductase. 772 97

A 2618-bp cDNA that encodes the human mitochondrial glycerol-3-phosphate dehydrogenase has been isolated from a HeLa cell cDNA library and the nucleotide sequence determined. An open reading frame encodes a protein of 727 amino acids that is 96% similar to the rat protein and, like the rat protein, contains sites homologous to the Ca(2+)-binding sites of calmodulin, as well as FAD- and putative glycerol-phosphate-binding sites.
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PMID:The sequence of a human mitochondrial glycerol-3-phosphate dehydrogenase-encoding cDNA. 782 23

The coenzyme specificity of Escherichia coli glutathione reductase was switched from NADP to NAD by modifying the environment of the 2'-phosphate binding site through a set of point mutations: A179G, A183G, V197E, R198M, K199F, H200D, and R204P (Scrutton NS, Berry A, Perham RN, 1990, Nature 343:38-43). In order to analyze the structural changes involved, we have determined 4 high-resolution crystal structures, i.e., the structures of the wild-type enzyme (1.86 A resolution, R-factor of 16.8%), of the wild-type enzyme ligated with NADP (2.0 A, 20.8%), of the NAD-dependent mutant (1.74 A, 16.8%), and of the NAD-dependent mutant ligated with NAD (2.2 A, 16.9%). A comparison of these structures reveals subtle differences that explain details of the specificity change. In particular, a peptide rotation occurs close to the adenosine ribose, with a concomitant change of the ribose pucker. The mutations cause a contraction of the local chain fold. Furthermore, the engineered NAD-binding site assumes a less rigid structure than the NADP site of the wild-type enzyme. A superposition of the ligated structures shows a displacement of NAD versus NADP such that the electron pathway from the nicotinamide ring to FAD is elongated, which may explain the lower catalytic efficiency of the mutant. Because the nicotinamide is as much as 15 A from the sites of the mutations, this observation reminds us that mutations may have important long-range consequences that are difficult to anticipate.
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PMID:Anatomy of an engineered NAD-binding site. 783 10

The effects of riboflavin and its derivatives such as FAD, FMN and lumichrome on the levels of high energy phosphate compounds (ATP and creatine phosphate) and intracellular pH in ischemic reperfused rat hearts were investigated using a Langendorff perfusion technique. 31P-NMR study showed a decrease in the levels of high energy phosphate compounds and pH values in myocardium after 30 min global ischemia and a slight recovery of these levels after a 30 min reperfusion following ischemia. However, in all the hearts perfused with riboflavin and its derivatives during ischemia-reperfusion, a marked recovery of high energy phosphate compounds and pH values were observed. In addition, the cardiac mitochondrial respiratory function was protected from ischemia-reperfusion injury. These results suggest that riboflavin, FAD, FMN, and lumichrome have a protective effect against ischemia-reperfusion injury to rat myocardium in vitro. It is assumed that these substances exert their effect directly in the extracellular space.
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PMID:Protective effects of riboflavin and its derivatives against ischemic reperfused damage of rat heart. 786 93


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