Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.3 (diaphorase)
 5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondria from a rodent malarial parasite (Plasmodium berghei) were successfully purified by differential centrifugation and 22% Percoll density gradient separation. The purified mitochondria from the erythrocytic stages of the parasite had a density of 1.05 and were found to be heterogeneous by transmission electron microscopy and rhodamine 123 fluorescence microscopy. Three marker enzymes, dihydroorotate dehydrogenase, cytochrome c reductase, and cytochrome c oxidase, were assessed during the organelle separation. Purification of cytochrome c oxidase was carried out from the purified mitochondria by using combination techniques of detergent solubilization and reduced cytochrome c-agarose affinity chromatography. The 560-fold purified enzyme with 3.6% yield was obtained and it had low catalytic efficiency with a kcat/Km of 5.9 x 10(-5) M-1 x min-1. The native form of the enzyme, determined by a gel filtration column on fast protein liquid chromatography, was found to be an oligomeric structure with a minimal molecular weight of 670 kDa. The malarial enzyme was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then compared to the enzyme obtained from host liver cells. These results suggested that the partially purified enzyme from the parasite was not different from its host mammalian cells. The importance of the enzyme in the erythrocytic phase of the parasite is discussed as a part of a simple electron transport system in mitochondrion linked to limited oxygen utilization and pyrimidine de novo biosynthesis.
 ...
PMID:Plasmodium berghei: partial purification and characterization of the mitochondrial cytochrome c oxidase. 839

A class of chromophore-modified anthracenediones with an additional pyrimidine ring incorporated into the chromophore system has been obtained in an attempt to provide compounds with diminished peroxidation activity and thus potentially lowered cardiotoxicity. Their synthesis was carried out by the reaction of 6-amino- or 6-hydroxy-7H-benzo[e]perimidin-7-one with a number of alkylamines. Potent activity was demonstrated in vitro against murine L1210 leukemia cells (equipotent with ametantrone) as well as against P388 leukemia in vivo (% T/C = 130-255). We observed that the benzoperimidines did not stimulate free radical formation, perhaps due to their poor substrate properties for NADH dehydrogenase.
 ...
PMID:6-[(aminoalkyl)amino]-substituted 7H-benzo[e]perimidin-7-ones as novel antineoplastic agents. Synthesis and biological evaluation. 842 Dec 88

In Salmonella enterica serovar Typhimurium, PurF-independent thiamine synthesis (or alternative pyrimidine biosynthesis) allows strains, under some growth conditions, to synthesize thiamine in the absence of the first step in the purine biosynthetic pathway. Mutations have been isolated in a number of loci that prevent this synthesis and thus result in an Apb(-) phenotype. Here we identify a new class of mutations that prevent PurF-independent thiamine synthesis and show that they are defective in the nuo genes, which encode the major, energy-generating NADH dehydrogenase of the cell. Data presented here indicated that a nuo mutant has reduced flux through the oxidative pentose phosphate pathway that may contribute to, but is not sufficient to cause, the observed thiamine requirement. We suggest that reduction of the oxidative pentose phosphate pathway capacity in a nuo mutant is an attempt to restore the ratio between reduced and oxidized pyridine nucleotide pools.
 ...
PMID:Lesions in the nuo operon, encoding NADH dehydrogenase complex I, prevent PurF-independent thiamine synthesis and reduce flux through the oxidative pentose phosphate pathway in Salmonella enterica serovar typhimurium. 1061 87

Mitochondria of the malaria parasite Plasmodium falciparum are morphologically different between the asexual and sexual blood stages (gametocytes). In this paper recent findings of mitochondrial heterogeneity are reviewed based on their ultrastructural characteristics, metabolic activities and the differential expression of their genes in these 2 blood stages of the parasite. The existence of NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), cytochrome c reductase (complex III) and cytochrome c oxidase (complex IV) suggests that the biochemically active electron transport system operates in this parasite. There is also an alternative electron transport branch pathway, including an anaerobic function of complex II. One of the functional roles of the mitochondrion in the parasite is the coordination of pyrimidine biosynthesis, the electron transport system and oxygen utilization via dihydroorotate dehydrogenase and coenzyme Q. Complete sets of genes encoding enzymes of the tricarboxylic acid cycle and the ATP synthase complex are predicted from P. falciparum genomics information. Other metabolic roles of this organelle include membrane potential maintenance, haem and coenzyme Q biosynthesis, and oxidative phosphorylation. Furthermore, the mitochondrion may be a chemotherapeutic target for antimalarial drug development. The antimalarial drug atovaquone targets the mitochondrion.
 ...
PMID:The multiple roles of the mitochondrion of the malarial parasite. 1555 97

alpha-Cyclopropyl-alpha-[p-methoxyphenyl]-5-pyrimidine methyl alcohol (ancymidol) is an inhibitor of ent-kaur-16-ene oxidation in microsomal preparations from the liquid endosperm of immature Marah macrocarpus seeds. The K(i) for this inhibitor is about 2 x 10(-9)m. Ancymidol also blocks ent-kaur-16-en-19-ol and ent-kaur-16-en-19-al oxidation by the same preparations with a similar efficiency, but does not significantly inhibit ent-kaur-16-en-19-oic acid oxidation. Ancymidol appears to be specific for this series of oxidations in higher plant tissues. It does not inhibit the oxidation of kaurene nor kaurenoic acid in rat liver microsomes and has no significant effect on the oxidation of cinnamic acid in microsomal preparations from Sorghum bicolor seedlings. Ancymidol also does not inhibit kaurene oxidation in vitro nor in vivo in cultures of the fungus Fusarium moniliforme. The presence of ancymidol did not significantly alter the activities of NADPH-cytochrome c reductase, NADH-cytochrome c reductase, or NADH-cytochrome b(5) reductase. The addition of ancymidol to suspensions of oxidized M. macrocarpus endosperm led to a difference spectrum with an absorption maximum at 427 nm and a minimum at 410 nm.
 ...
PMID:Studies on the Specificity and Site of Action of alpha-Cyclopropyl-alpha-[p-methoxyphenyl]-5-pyrimidine Methyl Alcohol (Ancymidol), a Plant Growth Regulator. 1666 May 61

CoQ (coenzyme Q), an isoprenylated benzoquinone, is a well-known component of the electron-transfer system in eukaryotes. The main role of CoQ is to transfer electrons from NADH dehydrogenase and succinate dehydrogenase to CoQ:cytochrome c reductase in the respiratory chain. However, recent evidence indicates that an involvement in respiration is not the only role of CoQ. The second apparent role of CoQ is its anti-oxidation property, and other novel roles for CoQ, such as in disulfide-bond formation, sulfide oxidation and pyrimidine metabolism, have been reported. CoQ10, having ten isoprene units in the isoprenoid side chain, has been used as a medicine and is now commercially popular as a food supplement. Two yeast species, namely the budding yeast Saccharomyces cerevisiae, which produces CoQ6, and the fission yeast Schizosaccharomyces pombe, which produces CoQ10, are the main subjects of the present minireview because they have greatly contributed to our basic knowledge of CoQ biosynthesis among eukaryotes. The biosynthetic pathway that converts p-hydroxybenzoate into CoQ consists of eight steps in yeasts. The five enzymes involved in the biosynthetic pathway have been identified in both yeasts, yet the functions of three proteins were still not known. Analyses of the biosynthetic pathway in yeasts also contribute to the understanding of human genetic diseases related to CoQ deficiency. In the present minireview I focus on the biochemical and commercial aspects of CoQ in yeasts and in other organisms for comparison.
 ...
PMID:Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms. 1953 Oct 29

1-Hydroxyquinolones as for example 1-hydroxy-2-dodecyl-4(1)quinolone (HDQ) are effective growth inhibitors for Toxoplasma gondii. These compounds were shown to interfere with the respiratory chain function by inhibition of type II NADH dehydrogenase activity. With the aid of partial drug resistant mutants we identified in this study the fourth enzyme of the de novo pyrimidine synthesis pathway, the T. gondii dihydroorotate dehydrogenase (TgDHODH), as an additional 1-hydroxyquinolone target. A single point mutation was found in the TgDHODH coding sequence of drug resistant clones that change a conserved Asn into Ser in the vicinity of the dihydroorotate binding site. This mutation is sufficient to confer the partial drug resistance phenotype as shown by allele replacement. Enzyme kinetics revealed that 1-hydroxyquinolones inhibit wild type TgDHODH with IC50s in the nanomolar range, while the IC50s for the N302S mutant were significantly increased. Furthermore, inhibition kinetics revealed that 1-hydroxyquinolones act as competitive inhibitors for the electron acceptor QD, but as uncompetitive inhibitors for dihydroorotate. Moreover, heterologous expression of the ubiquinone independent DHODH from Saccharomyces cerevisiae in T. gondii also leads to partial 1-hydroxyquinolone resistance. Our data suggest that inhibition of TgDHODH activity significantly contributes to the growth inhibiting potential of 1-hydroxyquinolones in T. gondii.
...
PMID:Identification of dihydroorotate dehydrogenase as a relevant drug target for 1-hydroxyquinolones in Toxoplasma gondii. 2374 78