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Hideto Miyoshi – One of the best experts on this subject based on the ideXlab platform.
Pinpoint Chemical Modification of Asp160 in the 49
kDa Subunit of Bovine Mitochondrial Complex I via a Combination of
Ligand-Directed Tosyl Chemistry and Click Chemistry, 2014Co-Authors: Takahiro Masuya, Masatoshi Murai, Hironobu Morisaka, Hideto MiyoshiAbstract:
a ligand-directed tosyl (LDT) chemistry strategy using
the synthetic Acetogenin ligand AL1, we succeeded in the pinpoint
alkynylation (−CCH) of Asp160 in the 49 kDa subunit
of bovine complex I, which may be located in the inner part of the
putative quinone binding cavity of the enzyme [Masuya, T., et al.
(2014) Biochemistry, 53, 2307–2317].
This study provided a promising technique for diverse chemical modifications
of complex I. To further improve this technique for its adaptation
to intact complex I, we here synthesized the new Acetogenin ligand
AL2, possessing an azido (−N3) group in place of
the terminal alkyne in AL1, and attempted the pinpoint azidation of
complex I in bovine heart submitochondrial particles. Careful proteomic
analyses revealed that, just as in the case of AL1, azidation occurred
at 49 kDa Asp160 with a reaction yield of ∼50%, verifying the
high site specificity of our LDT chemistry using Acetogenin ligands.
This finding prompted us to speculate that a reactivity of the azido
group incorporated into Asp160 (Asp160-N3) against externally
added chemicals can be employed to characterize the structural features
of the quinone/inhibitor binding cavity. Consequently, we used a ring-strained
cycloalkyne possessing a rhodamine fluorophore (TAMRA-DIBO), which
can covalently attach to an azido group via so-called click chemistry
without Cu1+ catalysis, as the reaction partner of Asp160-N3. We found that bulky TAMRA-DIBO is capable of reacting directly
with Asp160-N3 in intact complex I. Unexpectedly, the presence
of an excess amount of short-chain ubiquinones as well as some strong
inhibitors (e.g., quinazoline and fenpyroximate) did not interfere
with the reaction between TAMRA-DIBO and Asp160-N3; nevertheless,
bullatacin, a member of the natural Acetogenins, markedly interfered
with this reaction. Taking the marked bulkiness of TAMRA-DIBO into
consideration, it appears to be difficult to reconcile these results
with the proposal that only a narrow entry point accessing to the
quinone/inhibitor binding cavity exists in complex I [Baradaran, R.,
et al. (2013) Nature, 494, 443–448];
rather, they suggest that there may be another access path for TAMRA-DIBO
to the cavity
critical role of a methyl group on the γ lactone ring of annonaceous Acetogenins in the potent inhibition of mitochondrial complex iBioorganic & Medicinal Chemistry Letters, 2013Co-Authors: Naoto Kojima, Masato Abe, Yuki Suga, Kazufumi Ohtsuki, Tetsuaki Tanaka, Hiroki Iwasaki, Masayuki Yamashita, Hideto MiyoshiAbstract:
Abstract C34-epi and C34-epi-C35-trifluoro analogues of solamin, a mono-THF annonaceous Acetogenin, were synthesized. Their inhibitory activity, along with previously synthesized analogues (C35-fluoro, C35-difluoro, and C35-trifluorosolamins), against bovine mitochondrial NADH–ubiquinone oxidoreductase (complex I) was determined. The present study revealed that the methyl group on the γ-lactone moiety is critical to the potent inhibition of complex I by natural Acetogenins.
bis thf motif of Acetogenin binds to the third matrix side loop of nd1 subunit in mitochondrial nadh ubiquinone oxidoreductaseBiochimica et Biophysica Acta, 2011Co-Authors: Sayo Nakanishi, Masato Abe, Shuhei Yamamoto, Masatoshi Murai, Hideto MiyoshiAbstract:
Abstract Natural Acetogenins are among the most potent inhibitors of bovine heart mitochondrial NADH-ubiquinone oxidoreductase (complex I). Our photoaffinity labeling study suggested that the hydroxylated bis-THF ring moiety of Acetogenins binds at “site A” in the third matrix-side loop connecting the fifth and sixth transmembrane helices in the ND1 subunit [Kakutani et al. (2010) Biochemistry 49 , 4794–4803]. Nevertheless, since this proposition was led using a photoreactive Δlac-Acetogenin derivative, it needs to be directly verified using a natural Acetogenin-type probe. We therefore conducted photoaffinity labeling using a photoreactive natural Acetogenin mimic ([ 125 I] d i a zinylated n atural a cetogenin, [ 125 I]DANA), which has a small photolabile diazirine group, in place of a hydroxy group, attached to the bis-THF ring moiety. Analysis of the photocross-linked protein in bovine heart submitochondrial particles unambiguously revealed that [ 125 I]DANA binds to the membrane subunit ND1 with high specificity. The photocross-linking was completely blocked in the presence of just a 5-fold excess of bullatacin, indicating that [ 125 I]DANA is an excellent mimic of natural Acetogenins and hence binds to the site that accommodates natural products. Careful examination of the fragmentation patterns of the cross-linked ND1 generated by different proteases and their combinations indicated that the cross-linked residue is predominantly located at the supposed site A in the third matrix-side loop.
Jerry L Mclaughlin – One of the best experts on this subject based on the ideXlab platform.
Chemical defense in the zebra swallowtail butterfly, Eurytides marcellus, involving annonaceous AcetogeninsJournal of Natural Products, 1999Co-Authors: John M. Martin, Stephen R. Madigosky, Zhe-ming Gu, Dawei Zhou, Jinn Wu, Jerry L MclaughlinAbstract:
Few herbivores feed on the foliage of the North American paw paw tree, Asimina triloba; notable exceptions are the larvae of the zebra swallowtail butterfly, Eurytides marcellus. Toxic annonaceous Acetogenins, produced by A. triloba, are responsible for the relative unpalatability of the leaves. Acetogenins found in A. triloba extracts are potent pesticidal and antineoplastic agents and have emetic activity in vertebrates. In this study, partitioned aqueous MeOH fractions of the bioactive CH2Cl2 extracts, of freeze-dried and pulverized larvae, and of mature butterflies revealed Acetogenin content through the use of HPLC coupled to tandem MS (LC-MS/MS). This sensitive technique provides an uncomplicated method for the detection of trace compounds and, in this instance, has confirmed tissue presence of Acetogenins that serve a probable role as chemical defense agents against bird predation in zebra swallowtail larvae and adults.
Membrane conformations and their relation to cytotoxicity of asimicin and its analogues.Biochemistry, 1998Co-Authors: Hiroko Shimada, John B. Grutzner, John F. Kozlowski, Jerry L MclaughlinAbstract:
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.
the annonaceous Acetogenin bullatacin is cytotoxic against multidrug resistant human mammary adenocarcinoma cellsCancer Letters, 1997Co-Authors: Nicholas H Oberlies, Vicki L Croy, Marietta L Harrison, Jerry L MclaughlinAbstract:
Cytotoxic effects of the Annonaceous Acetogenin, bullatacin, were studied in multidrug-resistant (MDR) human mammary adenocarcinoma (MCF-7/Adr) cells vs. the parental non-resistant wild type (MCF-7/wt) cells. Bullatacin was effectively cytotoxic to the MCF-7/Adr cells while it was more cytostatic to the MCF-7/wt cells. ATP depletion is the mode of action of the Annonaceous Acetogenins, and these agents offer a special advantage in the chemotherapeutic treatment of MDR tumors that have ATP-dependent mechanisms.
William J Keller – One of the best experts on this subject based on the ideXlab platform.
Identification of annonaceous Acetogenins in the ripe fruit of the North American pawpaw ( Asimina triloba ).Journal of Agricultural and Food Chemistry, 2009Co-Authors: Kirk W. Pomper, Jeremiah D. Lowe, Sheri B. Crabtree, William J KellerAbstract:
The North American pawpaw [ Asimina triloba (L.) Dunal] is a tree fruit in the early stages of commercial production in the United States. This plant contains annonaceous Acetogenins in the twigs, unripe fruit, seeds, roots, and bark tissues, which display antitumor, pesticidal, antimalarial, anthelmintic, piscicidal, antiviral, and antimicrobial effects, suggesting many potentially useful applications. However, commercial development of these compounds, based on twig extracts, has been problematic due to limited availability of biomass for extraction. Additionally, Acetogenin compounds contained in fruit of pawpaw relatives (soursop or Annona muricata ) and tea made from the leaves of these plants may lead to an increased risk of atypical Parkinsonism later in life with overconsumption of these compounds. Therefore, the objectives of this study were (1) to determine if extracts of ripe pawpaw fruit pulp displayed Acetogenin activity, (2) to identify potential Acetogenin compounds in the fruit tissue, and (3) to determine if the Acetogenin activity varied in diverse pawpaw genotypes and closely related Annona species. Extracts of ripe fruit had total extract weights and bioactivity using the brine shrimp bioassay similar to those from ‘NC-1’ pawpaw twig tissue. Pulp from soursop, cherimoya, and several additional pawpaw cultivars (‘Mitchell’, ‘Overleese’, ‘NC-1′,’Zimmerman’, ‘Wells’, and ‘Sunflower’) also displayed bioactivity, but peach or banana pulp did not. Ripe pawpaw pulp extract subjected to HPLC-MS analysis identified three prominent Acetogenins: asimicin, bullatacin, and bullatalicin. This study points to pawpaw fruit pulp serving as a new biomass source for the extraction of Acetogenin compounds for product development. An assessment of the potential human health risk of overconsumption of fruit and Acetogenin bioavailability and degradation studies should be pursued.
identification of annonaceous Acetogenins in the ripe fruit of the north american pawpaw asimina trilobaJournal of Agricultural and Food Chemistry, 2009Co-Authors: Kirk W. Pomper, Jeremiah D. Lowe, Sheri B. Crabtree, William J KellerAbstract:
The North American pawpaw [Asimina triloba (L.) Dunal] is a tree fruit in the early stages of commercial production in the United States. This plant contains annonaceous Acetogenins in the twigs, unripe fruit, seeds, roots, and bark tissues, which display antitumor, pesticidal, antimalarial, anthelmintic, piscicidal, antiviral, and antimicrobial effects, suggesting many potentially useful applications. However, commercial development of these compounds, based on twig extracts, has been problematic due to limited availability of biomass for extraction. Additionally, Acetogenin compounds contained in fruit of pawpaw relatives (soursop or Annona muricata) and tea made from the leaves of these plants may lead to an increased risk of atypical Parkinsonism later in life with overconsumption of these compounds. Therefore, the objectives of this study were (1) to determine if extracts of ripe pawpaw fruit pulp displayed Acetogenin activity, (2) to identify potential Acetogenin compounds in the fruit tissue, and (…