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The trypanosome alternative oxidase: a potential drug target?

Published online by Cambridge University Press:  29 November 2016

STEFANIE K. MENZIES Open the ORCID record for STEFANIE K. MENZIES [Opens in a new window] ,
LINDSAY B. TULLOCH ,
GORDON J. FLORENCE  and
TERRY K. SMITH
STEFANIE K. MENZIES
Affiliation:
Biomedical Sciences Research Complex, University of St Andrews, St Andrews, Fife, Scotland KY16 9ST, UK
LINDSAY B. TULLOCH
Affiliation:
Biomedical Sciences Research Complex, University of St Andrews, St Andrews, Fife, Scotland KY16 9ST, UK
GORDON J. FLORENCE
Affiliation:
Biomedical Sciences Research Complex, University of St Andrews, St Andrews, Fife, Scotland KY16 9ST, UK
TERRY K. SMITH*
Affiliation:
Biomedical Sciences Research Complex, University of St Andrews, St Andrews, Fife, Scotland KY16 9ST, UK
*
*Corresponding author. Biomedical Sciences Research Complex, University of St Andrews, St Andrews, Fife, Scotland KY16 9ST, UK. E-mail: tks1@st-andrews.ac.uk
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Summary

New drugs against Trypanosoma brucei, the causative agent of Human African Trypanosomiasis, are urgently needed to replace the highly toxic and largely ineffective therapies currently used. The trypanosome alternative oxidase (TAO) is an essential and unique mitochondrial protein in these parasites and is absent from mammalian mitochondria, making it an attractive drug target. The structure and function of the protein are now well characterized, with several inhibitors reported in the literature, which show potential as clinical drug candidates. In this review, we provide an update on the functional activity and structural aspects of TAO. We then discuss TAO inhibitors reported to date, problems encountered with in vivo testing of these compounds, and discuss the future of TAO as a therapeutic target.

Keywords

Trypanosome alternative oxidasedrug discoverychemotherapyhuman African trypanosomiasissleeping sicknessTrypanosoma brucei
Type
Special Issue Review
Information
Parasitology , Volume 145 , Special Issue 2: Microbial protein targets: towards understanding and intervention , February 2018 , pp. 175 - 183
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Copyright
Copyright © Cambridge University Press 2016 

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References

REFERENCES

Ajayi, W., Chaudhuri, M. and Hill, G. C. (2002). Site-directed mutagenesis reveals the essentiality of the conserved residues in the putative diiron active site of the trypanosome alternative oxidase. Journal of Biological Chemistry 277, 8187–8193.Google Scholar
Andersson, M. E. and Nordlund, P. (1999). A revised model of the active site of alternative oxidase. FEBS Letters 449, 17–22.Google Scholar
Baker, N., de Koning, H. P., Mäser, P. and Horn, D. (2013). Drug resistance in African trypanosomiasis: the pelarsoprol and pentamidine story. Trends in Parasitology 29, 110–118.Google Scholar
Barrett, M. P., and Croft, S. L. (2012). Management of trypanosomiasis and leishmaniasis. British Medical Bulletin 104, 175–196.Google Scholar
Berthold, D. A., Andersson, M. E. and Nordlund, P. (2000). New insight into the structure and function of the alternative oxidase. Biochimica et Biophysica Acta 1460, 241–254.CrossRefGoogle ScholarPubMed
Berthold, D. A., Voevodskaya, N., Stenmark, P., Gräslund, A. and Nordlund, P. (2002). EPR studies of the mitochondrial alternative oxidase: evidence for a Diiron Carboxylate Center. Journal of Biological Chemistry 277, 43608–43614.Google Scholar
Bringaud, F., Barrett, M. P. and Zilberstein, D. (2012). Multiple roles of proline transport and metabolism in Trypanosomatids. Frontiers in Bioscience 17, 349–374.Google Scholar
Chaudhuri, M., and Hill, G. C. (1996). Cloning, sequencing and functional activity of the Trypanosoma brucei brucei alternative oxidase . Molecular and Biochemical Parasitology 83, 125–129.Google Scholar
Chaudhuri, M., Wilfred, A. and Hill, G. C. (1998). Biochemical and molecular properties of the Trypanosoma brucei alternative oxidase. Molecular and Biochemical Parasitology 95, 53–68.Google Scholar
Chaudhuri, M., Wilfred, A., Temple, S. and Hill, G. C. (1995). Identification and partial purification of a stage-specific 33 kDa mitochondrial protein as the alternative oxidase of the Trypanosoma brucei brucei bloodstream Trypomastigotes. The Journal of Eukaryotic Microbiology 42, 467–472.Google Scholar
Clarkson, A. B. and Brohn, F. H. (1976). Trypanosomiasis: an approach to chemotherapy by the inhibition of carbohydrate catabolism. Science (New York, N.Y.) 194, 204–206.Google Scholar
Clarkson, A. B., Bienensb, E. J., Pollakisz, G. and Gradyll, W. (1989). Respiration of bloodstream forms of the parasite Trypanosoma brucei brucei is dependent on a plant-like alternative oxidase. Journal of Biological Chemistry 264, 17770–17776.Google Scholar
Fang, J., and Beattie, D. S. (2003). Alternative oxidase present in Procyclic Trypanosoma brucei May act to lower the mitochondrial production of superoxide. Archives of Biochemistry and Biophysics 414, 294–302.Google Scholar
Fukai, Y., Amino, H., Hirawake, H., Yabu, Y., Ohta, N., Minagawa, N., Sakajo, S., Yoshimoto, A., Nagai, K., Takamiya, S., Kojima, S. and Kita, K. (1999). Functional expression of the Ascofuranone-sensitive Trypanosoma brucei Brucei alternative oxidase in the Cytoplasmic Membrane of Escherichia Coli. Comparative Biochemistry and Physiology. Part C, Pharmacology, Toxicology & Endocrinology 124, 141–148.Google Scholar
Fukai, Y., Coichi, N., Keisuke, K., Yoshisada, Y. and Suzuki, T. (2003). Overproduction of highly active trypanosome alternative oxidase in Escherichia coli heme-deficient mutant. Parasitology International 52, 237–2p41.Google Scholar
Grady, R. W., Bienen, E. J., Dieck, H. A., Saric, M. and Clarkson, A. B. (1993). N-N-alkyl-3,4-dihydroxybenzamides as inhibitors of the trypanosome alternative oxidase: activity in vitro and in vivo. Antimicrobial Agents and Chemotherapy 37, 1082–1085.Google Scholar
Grant, P. T. and Sargent, J. R. (1960). Properties of L-alpha-glycerophosphate oxidase and its role in the respiration of Trypanosoma Rhodesiense. The Biochemical Journal 76, 229–237.Google Scholar
Helfert, S., Estévez, A. M., Bakker, B., Michels, P. and Clayton, C. (2001). Roles of triosephosphate isomerase and Aerobic metabolism in Trypanosoma brucei . Biochemical Journal 357(Pt 1), 117–125.Google Scholar
Kido, Y., Shiba, T., Inaoka, D. K., Sakamoto, K., Nara, T., Aoki, T., Honma, T., Tanaka, A., Inoue, M., Matsuoka, S., Moore, A., Harada, S. and Kita, K. (2010). Crystallization and preliminary crystallographic analysis of cyanide-insensitive alternative oxidase from Trypanosoma brucei brucei . Acta Crystallographica Section F, Structural Biology and Crystallization Communications 66(Pt 3). International Union of Crystallography: 275–278.Google Scholar
Kuepfer, I., Schmid, C., Allan, M., Edielu, A., Haary, E. P., Kakembo, A., Kibona, S., Blum, J. and Burri, C. (2012). Safety and efficacy of the 10-day melarsoprol schedule for the treatment of second stage Rhodesiense sleeping sickness. PLoS Neglected Tropical Diseases 6, e16955.Google Scholar
Li, X. W., Herrmann, J., Zang, Y., Grellier, P., Prado, S., Muller, R. and Nay, B. (2013). Synthesis and biological activities of the respirator chain inhibitor aurachin D and new ring versus chain analogues. Beilstein Journal of Organic Chemistry 9(Figure 1), 1551–1558.Google Scholar
Lüscher, A., de Koning, H. P. and Mäser, P. (2007). Chemotherapeutic strategies against Trypanosoma brucei: drug targets vs. drug targeting. Current Pharmaceutical Design 13, 555–567.Google Scholar
Marechal, A., Kido, Y., Kita, K., Moore, A. L. and Rich, P. R. (2009). Three redox states of Trypanosoma brucei alternative oxidase identified by infrared spectroscopy and electrochemistry. Journal of Biological Chemistry 284, 31827–31833.Google Scholar
Minagawa, N., Yabu, Y., Kita, K., Nagai, K., Ohta, N., Meguro, K., Sakajo, S.and Yoshimoto, A. (1997). An antibiotic, Ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei . Molecular and Biochemical Parasitology 81, 127–136.Google Scholar
Mogi, T., Ui, H., Shiomi, K., Omura, S., Miyoshi, H. and Kita, K. (2009). Antibiotics LL-Z1272 identified as novel inhibitors discriminating bacterial and mitochondrial quinol oxidases. Biochimica et Biophysica Acta - Bioenergetics 1787, 129–133.Google Scholar
Moore, A. L., Carré, J. E., Affourtit, C., Albury, M. S., Crichton, P. G., Kita, K. and Heathcote, P. (2008). Compelling EPR evidence that the alternative oxidase is a diiron carboxylate protein. Article. Biochimica et Biophysica Acta 1777, 327–330.Google Scholar
Moore, A. L., Shiba, T., Young, L., Harada, S., Kita, K. and Ito, K. (2013). Unraveling the heater: new insights into the structure of the alternative oxidase. Annual Review of Plant Biology 64, 637–663.Google Scholar
Nakamura, K., Fujioka, S., Fukumoto, S., Inoue, N., Sakamoto, K., Hirata, H., Kido, Y., Yabu, Y., Suzuki, T., Watanabe, Y. I., Saimoto, H., Akiyama, H. and Kita, K. (2010). Trypanosome alternative oxidase, a potential therapeutic target for sleeping sickness, is conserved among Trypanosoma brucei subspecies. Parasitology International 59. Elsevier Ireland Ltd: 560–564.Google Scholar
Nihei, C., Fukai, Y. and Kita, K. (2002). Trypanosome alternative oxidase as a target of chemotherapy. Biochimica et Biophysica Acta – Molecular Basis of Disease 1587, 234–239.Google Scholar
Nihei, C., Fukai, Y., Kawai, K., Osanai, A., Yabu, Y., Suzuki, T., Ohta, N., Minagawa, N., Nagai, K. and Kita, K. (2003). Purification of active recombinant trypanosome alternative oxidase. FEBS Letters 538, 35–40.Google Scholar
Opperdoes, F. R., Borst, P. and Fonck, K. (1976). The potential use of inhibitors of glycerol-3-Phosphate oxidase for chemotherapy of African trypanosomiasis. FEBS Letters 62, 169–172.Google Scholar
Ott, R., Chibale, K., Anderson, S., Chipeleme, A., Chaudhuri, M., Guerrah, A., Colowick, N. and Hill, G. C. (2006). Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Acta Tropica 100, 172–184.Google Scholar
Pollakis, G., Grady, R. W., Dieck, H. A. and Clarkson, A. B. (1995). Competition between inhibitors of the trypanosome alternative oxidase (TAO) and reduced coenzyme Q9. Biochemical Pharmacology 50, 1207–1210.Google Scholar
Saimoto, H., Kido, Y., Haga, Y., Sakamoto, K. and Kita, K. (2013). Pharmacophore identification of Ascofuranone, potent inhibitor of cyanide-insensitive alternative oxidase of Trypanosoma brucei . Journal of Biochemistry 153, 267–273.Google Scholar
Schonbaum, G. R., Bonner, W. D., Storey, B. T. and Bahr, J. T. (1971). Specific inhibition of the cyanide-insensitive respiratory pathway in plant mitochondria by hydroxamic acids. Plant Physiology 47, 124–128.Google Scholar
Shiba, T., Kido, Y., Sakamoto, K., Ken, D., Tsuge, C. and Tatsumi, R. (2013). Structure of the trypanosome cyanide-insensitive alternative oxidase. Proceedings of the National Academy of Sciences 110, 4580–4585. doi:10.1073/pnas.1218386110/-/DCSupplemental. www.pnas.org/cgi/doi/10-1073/pnas.1218386110 Google Scholar
Simarro, P. P., Cecchi, G., Franco, J. R., Paone, M., Diarra, A., Ruiz-Postigo, J. A., Fèvre, E. M., Mattioli, R. C. and Jannin, J. G. (2012). Estimating and mapping the population at risk of sleeping sickness. PLoS Neglected Tropical Diseases 6, e1859.Google Scholar
Suzuki, T., Nihei, C. I., Yabu, Y., Hashimoto, T., Suzuki, M., Yoshida, A., Nagai, K., Hosokawa, T., Minagawa, N., Suzuki, S., Kita, K. and Ohta, N. (2004). Molecular cloning and characterization of Trypanosoma vivax alternative oxidase (AOX) gene, a target of the Trypanocide Ascofuranone. Parasitology International 53, 235–245.Google Scholar
Tsuda, A., Witola, W. H., Konnai, S., Ohashi, K. and Onuma, M. (2006). The effect of TAO expression on PCD-like phenomenon development and drug resistance in Trypanosoma brucei . Parasitology International 55, 135–142.Google Scholar
Vassella, E., Probst, M., Schneider, A., Studer, E., Renggli, C. K., and Roditi, I. (2004). Expression of a major surface protein of Trypanosoma brucei insect forms is controlled by the activity of mitochondrial enzymes. Molecular Biology of the Cell 15, 3986–3993.Google Scholar
Walker, R., Saha, L., Hill, G. C. and Chaudhuri, M. (2005). The effect of over-expression of the alternative oxidase in the procyclic forms of Trypanosoma brucei . Molecular and Biochemical Parasitology 139, 153–162.Google Scholar
World Health Organization (2013). Control and Surveillance of Human African Trypanosomiasis. World Health Organization Technical Report Series, no. 984: 1–237.Google Scholar
World Health Organization (2016). Human African Trypanosomiasis. http://apps.who.int/gho/data/node.main.A1635?lang=en.Google Scholar
Yabu, Y., Minagawa, N., Kita, K., Nagai, K., Honma, M., Sakajo, S., Koide, T., Ohta, N. and Yoshimoto, A. (1998). Oral and intraperitoneal treatment of Trypanosoma brucei brucei with a combination of Ascofuranone and glycerol in mice. Parasitology International 47, 131–137.Google Scholar
Yabu, Y., Yoshida, A., Suzuki, T., Nihei, C. I., Kawai, K., Minagawa, N., Hosokawa, T., Nagai, K., Kita, K. and Ohta, N. (2003). The efficacy of ascofuranone in a consecutive treatment on Trypanosoma brucei brucei in mice. Parasitology International 52, 155–164.Google Scholar
Yabu, Y., Suzuki, T., Nihei, C. I., Minagawa, N., Hosokawa, T., Nagai, K., Kita, K. and Ohta, N. (2006). Chemotherapeutic efficacy of ascofuranone in Trypanosoma vivax-infected mice without glycerol. Parasitology International 55, 39–43.Google Scholar
Zoltner, M., Horn, D., de Koning, H. P., and Field, M. C. (2016). Exploiting the Achilles’ Heel of membrane trafficking in trypanosomes. Current Opinion in Microbiology 34. Elsevier Ltd: 97–103.Google Scholar