Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dicoumarol, a competitive inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), increases intracellular superoxide and affects cell growth of tumor cells. This work was set to establish a mechanistic link between dicoumarol, superoxide and cell cycle alterations in HL-60 cells. Using ES936, a mechanism-based irreversible inhibitor of NQO1, we demonstrate that NQO1 inhibition is not a major factor involved in superoxide boost. Mitochondrial Complexes II, III and IV were directly inhibited by dicoumarol. Succinate, which inhibits superoxide generation by reversed electron flow in Complex II, significantly decreased superoxide boost in dicoumarol-treated cells and in isolated mitochondria incubated with dicoumarol and decylubiquinol. Superoxide generation in cells was strongly potentiated by blocking the quinone site of Complex II with thenoyltrifluoroacetone, supporting the involvement of cytochrome b560 to drive electrons for increasing superoxide. Simultaneous inhibition of the mitochondrial chain upstream ubiquinone and displacement of succinate from the Complex II active site is proposed as a major mechanism to explain how dicoumarol increases superoxide in HL-60 cells. Dicoumarol-treated cells accumulated in S phase due to the impairment of pyrimidine biosynthesis at dihydroorotate dehydrogenase step because blockade was overcome by addition of exogenous uridine or orotate, but not by dihydroorotate. We demonstrate for the first time that dicoumarol inhibits mitochondrial electron transport, induces superoxide release by reversed electron flow in Complex II, and inhibits pyrimidines biosynthesis. These actions must be taken into account when considering dicoumarol effects on cells.
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PMID:Dicoumarol impairs mitochondrial electron transport and pyrimidine biosynthesis in human myeloid leukemia HL-60 cells. 1712 68

While many functions of the p53 tumor suppressor affect mitochondrial processes, the role of altered mitochondrial physiology in a modulation of p53 response remains unclear. As mitochondrial respiration is affected in many pathologic conditions such as hypoxia and intoxications, the impaired electron transport chain could emit additional p53-inducing signals and thereby contribute to tissue damage. Here we show that a shutdown of mitochondrial respiration per se does not trigger p53 response, because inhibitors acting in the proximal and distal segments of the respiratory chain do not activate p53. However, strong p53 response is induced specifically after an inhibition of the mitochondrial cytochrome bc1 (the electron transport chain complex III). The p53 response is triggered by the deficiency in pyrimidines that is developed due to a suppression of the functionally coupled mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). In epithelial carcinoma cells the activation of p53 in response to mitochondrial electron transport chain complex III inhibitors does not require phosphorylation of p53 at Serine 15 or up-regulation of p14(ARF). Instead, our data suggest a contribution of NQO1 and NQO2 in stabilization of p53 in the nuclei. The results establish the deficiency in pyrimidine biosynthesis as the cause of p53 response in the cells with impaired mitochondrial respiration.
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PMID:Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway. 2064 86

Dihydroorotate:quinone oxidoreductases (DHOQOs) are membrane bound enzymes responsible for oxidizing dihydroorotate (DHO) to orotate with concomitant reduction of quinone to quinol. They have FMN as prosthetic group and are part of the monotopic quinone reductase superfamily. These enzymes are also members of the dihydroorotate dehydrogenases (DHODHs) family, which besides membrane bound DHOQOs, class 2, includes soluble enzymes which reduce either NAD+ or fumarate, class 1. As key enzymes in both the de novo pyrimidine biosynthetic pathway as well as in the energetic metabolism, inhibitors of DHOQOs have been investigated as leads for therapeutics in cancer, immunological disorders and bacterial/viral infections. This work is a thorough bioinformatic approach on the structural conservation and taxonomic distribution of DHOQOs. We explored previously established structural/functional hallmarks of these enzymes, while searching for uncharacterized common elements. We also discuss the cellular role of DHOQOs and organize the identified protein sequences within six sub-classes 2A to 2F, according to their taxonomic origin and sequence traits. We concluded that DHOQOs are present in Archaea, Eukarya and Bacteria, including the first recognition in Gram-positive organisms. DHOQOs can be the single dihydroorotate dehydrogenase encoded in the genome of a species, or they can coexist with other DHODHs, as the NAD+ or fumarate reducing enzymes. Furthermore, we show that the type of catalytic base present in the active site is not an absolute criterium to distinguish between class 1 and class 2 enzymes. We propose the existence of a quinone binding motif ("ExAH") adjacent to a hydrophobic cavity present in the membrane interacting N-terminal domain.
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PMID:Investigating the amino acid sequences of membrane bound dihydroorotate:quinone oxidoreductases (DHOQOs): Structural and functional implications. 3299 46