Search results for "respiratory chain"
showing 10 items of 96 documents
Synthesis of pyrido[2,1-a]isoquinolin-4-ones and oxazino[2,3-a]isoquinolin-4-ones: New inhibitors of mitochondrial respiratory chain
2013
International audience; Benzo[a]quinolizine is an important heterocyclic framework that can be found in numerous bioactive compounds. The general scheme for the synthesis of these compounds was based on the preparation of the appropriate dihydroisoquinolines by Bischler-Napieralski cyclization with good yields, followed by the Pemberton method to form the oxazinones or pyridones derivatives via acyl-ketene imine cyclocondensation. All the synthesized compounds were assayed in vitro for their ability to inhibit mitochondrial respiratory chain. Most of the tested compounds were able to inhibit the integrated electron transfer chain, measured as NADH oxidation, which includes complexes I, III …
NADH dehydrogenase deficiency results in low respiration rate and improved aerobic growth of Zymomonas mobilis.
2008
The respiratory chain of the ethanol-producing bacterium Zymomonas mobilis is able to oxidize both species of nicotinamide cofactors, NADH and NADPH. A mutant strain with a chloramphenicol-resistance determinant inserted in ndh (encoding an NADH : CoQ oxidoreductase of type II) lacked the membrane NADH and NADPH oxidase activities, while its respiratory d-lactate oxidase activity was increased. Cells of the mutant strain showed a very low respiration rate with glucose and no respiration with ethanol. The aerobic growth rate of the mutant was elevated; exponential growth persisted longer, resulting in higher biomass densities. For the parent strain a similar effect of aerobic growth stimulat…
Adaptive antioxidant methionine accumulation in respiratory chain complexes explains the use of a deviant genetic code in mitochondria
2008
Humans and most other animals use 2 different genetic codes to translate their hereditary information: the standard code for nuclear-encoded proteins and a modern variant of this code in mitochondria. Despite the pivotal role of the genetic code for cell biology, the functional significance of the deviant mitochondrial code has remained enigmatic since its first description in 1979. Here, we show that profound and functionally beneficial alterations on the encoded protein level were causative for the AUA codon reassignment from isoleucine to methionine observed in most mitochondrial lineages. We demonstrate that this codon reassignment leads to a massive accumulation of the easily oxidized …
A human multisystem disorder with autoinflammation, leukoencephalopathy and hepatopathy is caused by mutations in C2orf69
2021
AbstractBackgroundDeciphering the function of the many genes previously classified as uncharacterized “open reading frame” (orf) completes our understanding of cell function and its pathophysiology.MethodsWhole-exome sequencing, yeast 2-hybrid and transcriptome analyses together with molecular characterization are used here to uncover the function of the C2orf69 gene.ResultsWe identify loss-of-function mutations in the uncharacterized C2orf69 gene in eight individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localizatio…
Semisynthesis of antitumoral acetogenins: SAR of functionalized alkyl-chain bis-tetrahydrofuranic acetogenins, specific inhibitors of mitochondrial c…
2000
The acetogenins of Annonaceae are known by their potent cytotoxic activity. In fact, they are promising candidates as a new future generation of antitumoral drugs to fight against the current chemiotherapic resistant tumors. The main target enzyme of these compounds is complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial respiratory chain, a key enzymatic complex of energy metabolism. In an attempt to characterize the relevant structural factor of the acetogenins that determines the inhibitory potency against this enzyme, we have prepared a series of bis-tetrahydrofuranic acetogenins with different functional groups along the alkyl chain. They comprise several oxo, hydroxylimino,…
Cherimolin-1, New Selective Inhibitor of the First Energy-Coupling Site of the NADH:Ubiquinone Oxidoreductase (Complex I)
1997
The mechanism linking electron transport to proton translocation in the NADH:ubiquinone oxidoreductase (complex I of the mitochondrial respiratory chain) is still unclear. Inhibitors acting at different sites of the enzyme are powerful tools to clarify this mechanism. Up to now, a unique inhibitor, the Annonaceous acetogenin rolliniastatin-2, selectively blocks the most internal proton-translocation site. This study introduces cherimolin-1, a new acetogenin that inhibits the complex I with this special mode of action, which is more easily available from the plant material. Moreover, the mode of action of this scarce type of complex I inhibitor is further characterized.
Epoxy-Acetogenins and other Polyketide Epoxy Derivatives as Inhibitors of the Mitochondrial Respiratory Chain Complex I
2000
Annonaceous acetogenins (ACG), an extensive group of cytotoxic natural products, are antitumor agents whose main mode of action is inhibition of the mammalian mitochondrial complex I. Herein we describe the importance of the different chemical groups along the alkyl chain for optimal inhibitory potency, discussing the structurally relevant factors present in these compounds. For this purpose, a series of epoxide derivatives from alpha-linolenic acid were prepared and their activity compared with that of epoxy-acetogenins and tetrahydrofuranic (THF) acetogenins isolated from Rollinia membranacea.
Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I).
1994
Natural products from the plants of the family Annonaceae, collectively called Annonaceous acetogenins, are very potent inhibitors of the NADH-ubiquinone reductase (Complex I) activity of mammalian mitochondria. The properties of five of such acetogenins are compared with those of rotenone and piericidin, classical potent inhibitors of Complex I. Rolliniastatin-1 and rolliniastatin-2 are more powerful than piericidin in terms of both their inhibitory constant and the protein-dependence of their titre in bovine submitochondrial particles. These acetogenins could be considered therefore the most potent inhibitors of mammalian Complex I. Squamocin and otivarin also have an inhibitory constant …
Bisbenzyltetrahydroisoquinolines, a New Class of Inhibitors of the Mitochondrial Respiratory Chain Complex I
2004
Four bisbenzyltetrahydroisoquinoline alkaloids (-)-medelline, (+)-antioquine, (+)-aromoline, and (+)-obamegine were isolated from the fruits of Xylopia columbiana. These compounds, the previously isolated alkaloids (+)-thaligrisine and (+)-isotetrandrine, as well as their O-acetylated derivatives were assayed on submitochondrial particles from beef heart as inhibitors of the mammalian respiratory chain. The results revealed that these alkaloids act as selective inhibitors of mitochondrial complex I in a 0.15 - 4.71 microM range. O-Acetylation, which increases their lipophilicity, considerably increased the inhibitory potency.
Specific interactions of monotetrahydrofuranic annonaceous acetogenins as inhibitors of mitochondrial complex I.
2000
Annonaceous acetogenins (ACG) are a wide group of cytotoxic compounds isolated from plants of the Annonaceae family. Some of them are promising candidates to be a future new generation of antitumor drugs due to the ability to inhibit the NADH:ubiquinone oxidoreductase of the respiratory chain (mitochondrial complex I), main gate of the energy production in the cell. ACG are currently being tested on standard antitumor trials although little is known about the structure activity relationship at the molecular level. On recent studies, the relevance of several parts of the molecule for the inhibitory potency has been evaluated. Due to the great diversity of skeletons included in this family of…