The efficacy of ascofuranone in a consecutive treatment on Trypanosoma brucei brucei in mice

Yabu, Yoshisada; Yoshida, Ayako; Suzuki, Takashi; Nihei, Coh-ichi; Kawai, Keisuke; Minagawa, Nobuko; Hosokawa, Tomoyoshi; Nagai, Kazuo; Kita, Kiyoshi; Ohta, Nobuhiro

doi:10.1016/s1383-5769(03)00012-6

Cited by 78 publications

(60 citation statements)

References 38 publications

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“…Indeed, we have previously reported that the antibiotic ascofuranone (AF), isolated from the pathogenic fungus Ascochyta viciae, specifically inhibits the quinol oxidase activity of TAO at subnanomolar concentrations and rapidly kills the parasites (10). Furthermore, we have confirmed the chemotherapeutic efficacy of ascofuranone in vivo (11,12).…”

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confidence: 59%

Structure of the trypanosome cyanide-insensitive alternative oxidase

Shiba¹,

Kido²,

Sakamoto³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In addition to haem copper oxidases, all higher plants, some algae, yeasts, molds, metazoans, and pathogenic microorganisms such as Trypanosoma brucei contain an additional terminal oxidase, the cyanide-insensitive alternative oxidase (AOX). AOX is a diiron carboxylate protein that catalyzes the four-electron reduction of dioxygen to water by ubiquinol. In T. brucei, a parasite that causes human African sleeping sickness, AOX plays a critical role in the survival of the parasite in its bloodstream form. Because AOX is absent from mammals, this protein represents a unique and promising therapeutic target. Despite its bioenergetic and medical importance, however, structural features of any AOX are yet to be elucidated. Here we report crystal structures of the trypanosomal alternative oxidase in the absence and presence of ascofuranone derivatives. All structures reveal that the oxidase is a homodimer with the nonhaem diiron carboxylate active site buried within a four-helix bundle. Unusually, the active site is ligated solely by four glutamate residues in its oxidized inhibitor-free state; however, inhibitor binding induces the ligation of a histidine residue. A highly conserved Tyr220 is within 4 Å of the active site and is critical for catalytic activity. All structures also reveal that there are two hydrophobic cavities per monomer. Both inhibitors bind to one cavity within 4 Å and 5 Å of the active site and Tyr220, respectively. A second cavity interacts with the inhibitor-binding cavity at the diiron center. We suggest that both cavities bind ubiquinol and along with Tyr220 are required for the catalytic cycle for O 2 reduction. diiron protein | neglected tropical diseases | monotopic membrane protein | drug target | ubiquinol oxidase

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mentioning

confidence: 59%

Structure of the trypanosome cyanide-insensitive alternative oxidase

Shiba¹,

Kido²,

Sakamoto³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

153

209

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“…Due to the reliance of bloodstream-form African trypanosomes on glycolysis, coupled to the glycerol-3-phosphate oxidation required to regenerate NAD + , TAO has been proposed to be a candidate drug target (Yabu et al 2003 ;Chaudhuri et al 2006). However, computer modelling of metabolic flux and RNAi-mediated depletion of TAO suggests, in vitro, that the TAO protein would have to be inhibited by more than 95 % for there to be a significant effect on trypanosome growth (Helfert et al 2001).…”

Section: Trypanosome Alternative Oxidase (Tao)mentioning

confidence: 99%

“…However, computer modelling of metabolic flux and RNAi-mediated depletion of TAO suggests, in vitro, that the TAO protein would have to be inhibited by more than 95 % for there to be a significant effect on trypanosome growth (Helfert et al 2001). In T. brucei, TAO inhibition is only lethal when coupled with administration of glycerol to block glycerol-phosphate dehydrogenase or with repeated administration of the inhibitor (Yabu et al 1998(Yabu et al , 2003. Nevertheless, the demonstration that inhibitor treatment can cure mice suggests that the TAO may be a viable drug target.…”

Section: Trypanosome Alternative Oxidase (Tao)mentioning

confidence: 99%

Iron metabolism in trypanosomatids, and its crucial role in infection

Taylor

Kelly

2010

Parasitology

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Iron is almost ubiquitous in living organisms due to the utility of its redox chemistry. It is also dangerous as it can catalyse the formation of reactive free radicals -a classical double-edged sword. In this review, we examine the uptake and usage of iron by trypanosomatids and discuss how modulation of host iron metabolism plays an important role in the protective response. Trypanosomatids require iron for crucial processes including DNA replication, antioxidant defence, mitochondrial respiration, synthesis of the modified base J and, in African trypanosomes, the alternative oxidase. The source of iron varies between species. Bloodstream-form African trypanosomes acquire iron from their host by uptake of transferrin, and Leishmania amazonensis expresses a ZIP family cation transporter in the plasma membrane. In other trypanosomatids, iron uptake has been poorly characterized. Iron-withholding responses by the host can be a major determinant of disease outcome. Their role in trypanosomatid infections is becoming apparent. For example, the cytosolic sequestration properties of NRAMP1, confer resistance against leishmaniasis. Conversely, cytoplasmic sequestration of iron may be favourable rather than detrimental to Trypanosoma cruzi. The central role of iron in both parasite metabolism and the host response is attracting interest as a possible point of therapeutic intervention.

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“…In this respect it is interesting to note that ascofuranone, isolated from the pathogenic fungus Ascochyta visiae, specifically and potently inhibits the quinol oxidase activity of TAO (11) and rapidly kills the parasites. In addition, the chemotherapeutic efficacy of ascofuranone in vivo has been confirmed (12).…”

mentioning

confidence: 90%

Three Redox States of Trypanosoma brucei Alternative Oxidase Identified by Infrared Spectroscopy and Electrochemistry

Maréchal

Kido

Kita

et al. 2009

Journal of Biological Chemistry

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Electrochemistry coupled with Fourier transform infrared (IR) spectroscopy was used to investigate the redox properties of recombinant alternative ubiquinol oxidase from Trypanosoma brucei, the organism responsible for African sleeping sickness.Stepwise reduction of the fully oxidized resting state of recombinant alternative ubiquinol oxidase revealed two distinct IR redox difference spectra. The first of these, signal 1, titrates in the reductive direction as an n ‫؍‬ 2 Nernstian component with an apparent midpoint potential of 80 mV at pH 7.0. However, reoxidation of signal 1 in the same potential range under anaerobic conditions did not occur and only began with potentials in excess of 500 mV. Reoxidation by introduction of oxygen was also unsuccessful. Signal 1 contained clear features that can be assigned to protonation of at least one carboxylate group, further perturbations of carboxylic and histidine residues, bound ubiquinone, and a negative band at 1554 cm ؊1 that might arise from a radical in the fully oxidized protein. A second distinct IR redox difference spectrum, signal 2, appeared more slowly once signal 1 had been reduced. This component could be reoxidized with potentials above 100 mV. In addition, when both signals 1 and 2 were reduced, introduction of oxygen caused rapid oxidation of both components. These data are interpreted in terms of the possible active site structure and mechanism of oxygen reduction to water.Mitochondria from many higher plants possess, in addition to the conventional cytochrome c oxidase, a second terminal oxidase that oxidizes ubiquinol (1-3). In thermogenic plants this alternative oxidase (AOX) 6 plays a key role in the release of heat for pollination purposes or for maintaining a warm environment within the flower at low ambient temperatures. In nonthermogenic plants its function is still under debate; proposed roles include maintaining tricarboxylic acid cycle turnover under high cytosolic phosphorylation potentials, defense against oxidative stress, and growth rate and energy charge homeostasis (4). AOX is also found in species of fungi, green algae, bacteria, and protozoa (5) and, more recently, in mollusks, nematodes, and chordates (6). Of particular importance, however, is its presence in pathogenic protozoa such as the blood parasite Trypanosoma brucei (7) and the intestinal parasite Cryptosporidium parvum (8, 9). T. brucei is a parasite that causes African sleeping sickness in humans and Nagana in livestock and is transmitted by the tsetse fly (7). The bloodstream forms of T. brucei appear to depend solely on its alternative oxidase (TAO) for respiration. Because the protein is absent from the mammalian host, TAO is an attractive and important chemotherapeutic target for African trypanosomiasis (7-10). In this respect it is interesting to note that ascofuranone, isolated from the pathogenic fungus Ascochyta visiae, specifically and potently inhibits the quinol oxidase activity of TAO (11) and rapidly kills the parasites. In addition, the chemotherapeutic eff...

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The efficacy of ascofuranone in a consecutive treatment on Trypanosoma brucei brucei in mice

Cited by 78 publications

References 38 publications

Structure of the trypanosome cyanide-insensitive alternative oxidase

Structure of the trypanosome cyanide-insensitive alternative oxidase

Iron metabolism in trypanosomatids, and its crucial role in infection

Three Redox States of Trypanosoma brucei Alternative Oxidase Identified by Infrared Spectroscopy and Electrochemistry

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