Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bullatacin, a compound isolated from plants of the Annonaceae, and its analogues show in vivo potential as antitumor agents based on their efficacy in normal mice bearing L1210 murine leukemia and athymic mice bearing A2780 conventional ovarian cancer xenografts. These compounds also have interesting potential as insecticides and inhibit respiration in insect-derived Sf9 cells with high potency. Their toxicity in both cases probably arises from their strong inhibition of mitochondrial electron transport with a specific action at complex I.
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PMID:Mode of action of bullatacin: a potent antitumor and pesticidal annonaceous acetogenin. 837 27

The Annonaceous acetogenins represent a class of compounds with diverse bioactivities, including promising cytotoxicites. These are due, at least in part, to inhibition of complex I in the oxidative phosphorylation pathway in mitochondria. Fourteen Annonaceous acetogenins were tested in a rat liver mitochondrial oxygen uptake assay to probe additional structure-activity relationships. In this subcellular assay, the activity of non-adjacent bis-THF ring acetogenins depends on the distance between the two THF rings; the activity decreases to that of a mono-THF ring acetogenin if the distance is too long. When one THF ring is replaced with a tetrahydropyran ring, the activity remains comparable. The configuration of the THF ring, in mono ring compounds, seems to be more important than stereochemical differences in the rings of adjacent bis-THF ring compounds. Bullatacin, an adjacent bis-THF ring acetogenin, was used as a standard compound in every run to normalize the data.
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PMID:SARs of annonaceous acetogenins in rat liver mitochondria. 888 49

Certain plant species belonging to the family Annonaceae produce Annonaceous acetogenins, which are a unique class of long-chain fatty acid derivatives with potent cytotoxicity. Putative protein targets of the acetogenins are membrane-associated proteins, including complex I. Asimicin and its analogues constitute a class of Annonaceous acetogenins containing two tetrahydrofuran (THF) rings with hydrocarbon chains tethered to each ring; an alpha,beta-unsaturated gamma-lactone ring is terminal to one of the alkyl chains. The compounds examined in this study differ in the length of the alkyl chain between the THF rings and the lactone ring. The positions of both the THF and the lactone rings within liposomal membranes were determined by proton (1H) nuclear magnetic resonance spectroscopy. The depth of membrane penetration of acetogenins, coupled to membrane diffusion, controls the conformation of acetogenins as they diffuse to an active site. Based on 1H intermolecular nuclear Overhauser effects (NOEs), the THF rings of all acetogenins studied reside near the polar interfacial head group region of the DMPC. This was corroborated by 1H two-dimensional NOE spectroscopy and differential scanning calorimetry studies. The 1H difference NOE spectra indicated that the lactone rings of asimicin and parviflorin, the latter of which has two fewer carbons in its alkyl chain, are located below the glycerol backbone in the membrane. In contrast with asimicin and parviflorin, the lactone ring of longimicin B, an asimicin analogue with an alkyl chain four carbons shorter, resides close to the midplane in the membrane. This was corroborated by manganese-induced broadening studies. Since the THF rings are located near the center of the acetogenin molecules and the lactone ring is terminal to a long alkyl chain, these observations indicate that an asimicin-type acetogenin can be in either sickle-shaped or U-shaped conformations, depending on the length of the alkyl chain between the THF rings and the lactone ring. Interestingly, longimicin B does not exhibit significant cytotoxicity, but parviflorin is as cytotoxic as asimicin. The cytotoxicity of the asimicin-type of acetogenins would seem to be strongly related to the membrane conformation. This is the first report elucidating the conformation of Annonaceous acetogenins in membranes.
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PMID:Membrane conformations and their relation to cytotoxicity of asimicin and its analogues. 945 75