Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-745bb68f8f-g4j75 Total loading time: 0 Render date: 2025-02-05T22:48:05.307Z Has data issue: false hasContentIssue false

6 - Targets in Amitochondrial Protists

Published online by Cambridge University Press:  11 August 2009

Tag E. Mansour
With
Joan MacKinnon Mansour
Tag E. Mansour
Affiliation:
Stanford University, California
Get access

Summary

Biology of Amitochondrial Protists

The parasitic protozoa discussed in this chapter are grouped together on the basis of the nature of their fermentative energy metabolism. In addition to having no mitochondria, they undergo no cytochrome-mediated electron transport and no oxidative phosphorylation processes. These organisms, which do not live intracellularly, have metabolically adapted to survive under strictly anaerobic conditions or under low levels of oxygen tension in the lumen of the gut or in the vagina of their hosts. They are represented here by Entamoeba histolytica, Giardia intestinalis, and Trichomonas vaginalis. All these parasites are aerotolerant and take up O2 that is present in their natural habitat. The O2 does not appear to be involved in energy production but is used as a means of detoxifying potentially noxious or toxic materials in their environment (Coombs & Muller, 1995). Looking at them from the evolutionary point of view they appear to have evolved at a time when life was predominantly anaerobic and mitochondria were unknown. Because of this and other metabolic differences there is a view that amitochondrial eukaryotes have separated early from the main trunk of eukaryotic evolution (Muller, 1988). However, a report by Mertens et al. (1998) on the marked diversity of pyrophosphate-dependent PFK sequences of some protists makes this conclusion less certain. These organisms have pyruvate:ferredoxin oxidoreductases that function as electron transport proteins. Others, especially Trichomonas spp., have developed new organelles called hydrogenosomes, which are compartments for energy metabolism.

Type
Chapter
Information
Chemotherapeutic Targets in Parasites
Contemporary Strategies
 , pp. 129 - 155
Publisher: Cambridge University Press
Print publication year: 2002

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ankri, S., Miron, T., Rabinkov, A., Wilchek, M. & Mirelman, D. (1997). Allicin from garlic strongly inhibits cysteine proteinases and cytopathic effects of Entamoeba histolytica. Antimicrob Agents Chemother, 41(10), 2286–2288Google ScholarPubMed
Broom, A. D. (1989). Rational design of enzyme inhibitors: Multisubstrate analogue inhibitors. J Med Chem, 32(1), 2–7CrossRefGoogle ScholarPubMed
Brown, D. M., Upcroft, J. A., Dodd, H. N., Chen, N. & Upcroft, P. (1999). Alternative 2-keto acid oxidoreductase activities in Trichomonas vaginalis. Mol Biochem Parasitol, 98(2), 203–214CrossRefGoogle ScholarPubMed
Bruchhaus, I. & Tannich, E. (1994). Purification and molecular characterization of the NAD(+)-dependent acetaldehyde/alcohol dehydrogenase from Entamoeba histolytica. Biochem J, 303(Pt 3), 743–748CrossRefGoogle ScholarPubMed
Bruchhaus, I., Jacobs, T., Denart, M. & Tannich, E. (1996). Pyrophosphate-dependent phosphofructokinase of Entamoeba histolytica: Molecular cloning, recombinant expression and inhibition by pyrophosphate analogues. Biochem J, 316(Pt 1), 57–63CrossRefGoogle ScholarPubMed
Byington, C. L., Dunbrack, R. L. Jr., Whitby, F. G., Cohen, F. E. & Agabian, N. (1997). Entamoeba histolytica: Computer-assisted modeling of phosphofructokinase for the prediction of broad-spectrum antiparasitic agents. Exp Parasitol, 87(3), 194–202CrossRefGoogle ScholarPubMed
Chevalier, A. (1996). The Encyclopedia of Medicinal Plants (pp. 21, 56). New York: DK Publishing, Inc
Chi, A. S. & Kemp, R. G. (2000). The primordial high energy compound: ATP or inorganic pyrophosphate? J Biol Chem, 275(46), 35677–35679CrossRefGoogle ScholarPubMed
Collins, K. D. & Stark, G. R. (1969). Aspartate transcarbamylase. Studies of the catalytic subunit by ultraviolet difference spectroscopy. J Biol Chem, 244(7), 1869–1877Google ScholarPubMed
Collins, K. D. & Stark, G. R. (1971). Aspartate transcarbamylase. Interaction with the transition state analogue N-(phosphonacetyl)-L-aspartate. J Biol Chem, 246(21), 6599–6605Google ScholarPubMed
Coombs, G. & Muller, M. (1995). Energy metabolism in anaerobic protozoa. In J. Marr & M. Muller (Eds.), Biochemistry and Molecular Biology of Parasites (pp. 33–48). San Diego: Academic PressCrossRef
Cosar, C. & Julou, L. (1959). Activite de L′(hydroxy-2′ethyl)-1 methyl-2nitro-5 imidazole (8.823 R. P.) vis-a-vis des infections experimentales a trichomonas vaginalis. Ann l'Institute Pasteur, 96, 238–241Google Scholar
Dan, M., Wang, A. L. & Wang, C. C. (2000). Inhibition of pyruvate-ferredoxin oxidoreductase gene expression in Giardia lamblia by a virus-mediated hammerhead ribozyme. Mol Microbiol, 36(2), 447–456CrossRefGoogle ScholarPubMed
Deng, Z., Huang, M., Singh, K., Albach, R. A., Latshaw, S. P., Chang, K. P. & Kemp, R. G. (1998). Cloning and expression of the gene for the active PPi-dependent phosphofructokinase of Entamoeba histolytica. Biochem J, 329(Pt 3), 659–664CrossRefGoogle ScholarPubMed
Diamond, L. S., Harlow, D. R. & Cunnick, C. C. (1978). A new medium for the axenic cultivation of Entamoeba histolytica and other Entamoeba. Trans R Soc Trop Med Hyg, 72(4), 431–432CrossRefGoogle ScholarPubMed
Docampo, R. (1990). Sensitivity of parasites to free radical damage by antiparasitic drugs. Chem Biol Interact, 73(1), 1–27CrossRefGoogle ScholarPubMed
Edwards, D. I. (1986). Reduction of nitroimidazoles in vitro and DNA damage. Biochem Pharmacol, 35(1), 53–58CrossRefGoogle ScholarPubMed
Edwards, M. R., Gilroy, F. V., Jimenez, B. M. & O'Sullivan, W. J. (1989). Alanine is a major end product of metabolism by Giardia lamblia: A proton nuclear magnetic resonance study. Mol Biochem Parasitol, 37(1), 19–26CrossRefGoogle ScholarPubMed
Edwards, M. R., Schofield, P. J., O'Sullivan, W. J. & Costello, M. (1992). Arginine metabolism during culture of Giardia intestinalis. Mol Biochem Parasitol, 53(1–2), 97–103CrossRefGoogle ScholarPubMed
Eubank, W. B. & Reeves, R. E. (1982). Analog inhibitors for the pyrophosphate-dependent phosphofructokinase of Entamoeba histolytica and their effect on culture growth. J Parasitol, 68(4), 599–602CrossRefGoogle ScholarPubMed
Evans, P. R., Farrants, G. W. & Hudson, P. J. (1981). Phosphofructokinase: Structure and control. Phil Trans R Soc London B Biol Sci, 293(1063), 53–62CrossRefGoogle ScholarPubMed
Finlay, B. & Fenchel, T. (1989). Hydrogenosomes in some anaerobic protozoa resemble mitochondria. FEMS Microbiol Lett, 65, 311–314CrossRefGoogle Scholar
Goldman, P., Koch, R. L., Yeung, T. C., Chrystal, E. J., Beaulieu, B. B. Jr., McLafferty, M. A. & Sudlow, G. (1986). Comparing the reduction of nitroimidazoles in bacteria and mammalian tissues and relating it to biological activity. Biochem Pharmacol, 35(1), 43–51CrossRefGoogle ScholarPubMed
Herzberg, O., Chen, C. C., Kapadia, G., McGuire, M., Carroll, L. J., Noh, S. J. & Dunaway-Mariano, D. (1996). Swiveling-domain mechanism for enzymatic phosphotransfer between remote reaction sites. Proc Natl Acad Sci USA, 93(7), 2652–2657CrossRefGoogle ScholarPubMed
Hrdy, I. & Muller, M. (1995). Primary structure and eubacterial relationships of the pyruvate:ferredoxin oxidoreductase of the amitochondriate eukaryote Trichomonas vaginalis. J Mol Evol, 41(3), 388–396CrossRefGoogle ScholarPubMed
Hrdy, I., Mertens, E. & Nohynkova, E. (1993). Giardia intestinalis: Detection and characterization of a pyruvate phosphate dikinase. Exp Parasitol, 76(4), 438–441CrossRefGoogle ScholarPubMed
Hrdy, I., Mertens, E. & Schaftingen, E. (1993). Identification, purification and separation of different isozymes of NADP-specific malic enzyme from Tritrichomonas foetus. Mol Biochem Parasitol, 57(2), 253–260CrossRefGoogle ScholarPubMed
Irvine, J. W., North, M. J. & Coombs, G. H. (1997). Use of inhibitors to identify essential cysteine proteinases of Trichomonas vaginalis. FEMS Microbiol Lett, 149(1), 45–50CrossRefGoogle ScholarPubMed
Johnson, P. (1993). Metronidazole and drug resistance. Parasitol Today, 9, 183–186CrossRefGoogle ScholarPubMed
Johnson, P. J., d'Oliveira, C. E., Gorrell, T. E. & Muller, M. (1990). Molecular analysis of the hydrogenosomal ferredoxin of the anaerobic protist Trichomonas vaginalis. Proc Natl Acad Sci USA, 87(16), 6097–6101CrossRefGoogle ScholarPubMed
Kelsall, B. L. & Ravdin, J. I. (1993). Degradation of human IgA by Entamoeba histolytica. J Infect Dis, 168(5), 1319–1322CrossRefGoogle ScholarPubMed
Krause, K. L., Volz, K. W. & Lipscomb, W. N. (1985). Structure at 2.9-A resolution of aspartate carbamoyltransferase complexed with the bisubstrate analogue N-(phosphonacetyl)-L-aspartate. Proc Natl Acad Sci USA, 82(6), 1643–1647CrossRefGoogle ScholarPubMed
Kulda, J. (1999). Trichomonads, hydrogenosomes and drug resistance. Int J Parasitol, 29(2), 199–212CrossRefGoogle ScholarPubMed
Kumar, A., Shen, P. S., Descoteaux, S., Pohl, J., Bailey, G. & Samuelson, J. (1992). Cloning and expression of an NADP(+)-dependent alcohol dehydrogenase gene of Entamoeba histolytica. Proc Natl Acad Sci USA, 89(21), 10188–10192CrossRefGoogle ScholarPubMed
LaRusso, N. F., Tomasz, M., Muller, M. & Lipman, R. (1977). Interaction of metronidazole with nucleic acids in vitro. Mol Pharmacol, 13(5), 872–882Google ScholarPubMed
Lindmark, D. G. & Muller, M. (1976). Antitrichomonad action, mutagenicity, and reduction of metronidazole and other nitroimidazoles. Antimicrob Agents Chemother, 10(3), 476–482CrossRefGoogle ScholarPubMed
Liu, S. M., Brown, D. M., O'Donoghue, P., Upcroft, P. & Upcroft, J. A. (2000). Ferredoxin involvement in metronidazole resistance of Giardia duodenalis. Mol Biochem Parasitol, 108(1), 137–140CrossRefGoogle ScholarPubMed
Lloyd, D. & Pedersen, J. Z. (1985). Metronidazole radical anion generation in vivo in Trichomonas vaginalis: Oxygen quenching is enhanced in a drug-resistant strain. J Gen Microbiol, 131(Pt 1), 87–92Google Scholar
Lloyd, D., Yarlett, N. & Yarlett, N. C. (1986). Inhibition of hydrogen production in drug-resistant and susceptible Trichomonas vaginalis strains by a range of nitroimidazole derivatives. Biochem Pharmacol, 35(1), 61–64CrossRefGoogle ScholarPubMed
Lo, H. S. & Reeves, R. E. (1978). Pyruvate-to-ethanol pathway in Entamoeba histolytica. Biochem J, 171(1), 225–230CrossRefGoogle ScholarPubMed
Mallinson, D. J., Lockwood, B. C., Coombs, G. H. & North, M. J. (1994). Identification and molecular cloning of four cysteine proteinase genes from the pathogenic protozoon Trichomonas vaginalis. Microbiology, 140(Pt 10), 2725–2735CrossRefGoogle ScholarPubMed
Martin, W. & Muller, M. (1998). The hydrogen hypothesis for the first eukaryote. Nature, 392(6671), 37–41[See comments.]CrossRefGoogle ScholarPubMed
McLaughlin, J. & Aley, S. (1985). The biochemistry and functional morphology of the Entamoeba. J Protozool, 32(2), 221–240CrossRefGoogle ScholarPubMed
McLaughlin, J., Lindmark, D. G. & Muller, M. (1978). Inorganic pyrophosphatase and nucleoside diphosphatase in the parasitic protozoon, Entamoeba histolytica. Biochem Biophys Res Commun, 82(3), 913–920CrossRefGoogle ScholarPubMed
Meng, E. C., Gschwend, D. A., Blaney, J. M. & Kuntz, I. D. (1993). Orientational sampling and rigid-body minimization in molecular docking. Proteins, 17(3), 266–278CrossRefGoogle ScholarPubMed
Mertens, E. (1993). Glycolysis revisited in parasitic protists. Parasitol Today, 9, 122–126CrossRefGoogle ScholarPubMed
Mertens, E., Schaftingen, E. & Muller, M. (1992). Pyruvate kinase from Trichomonas vaginalis, an allosteric enzyme stimulated by ribose 5-phosphate and glycerate 3-phosphate. Mol Biochem Parasitol, 54(1), 13–20CrossRefGoogle ScholarPubMed
Mertens, E., Ladror, U. S., Lee, J. A., Miretsky, A., Morris, A., Rozario, C., Kemp, R. G. & Muller, M. (1998). The pyrophosphate-dependent phosphofructokinase of the protist, Trichomonas vaginalis, and the evolutionary relationships of protist phosphofructokinases. J Mol Evol, 47(6), 739–750CrossRefGoogle ScholarPubMed
Minotto, L., Tutticci, E. A., Bagnara, A. S., Schofield, P. J. & Edwards, M. R. (1999). Characterisation and expression of the carbamate kinase gene from Giardia intestinalis. Mol Biochem Parasitol, 98(1), 43–51CrossRefGoogle ScholarPubMed
Mirelman, D., Monheit, D. & Varon, S. (1987). Inhibition of growth of Entamoeba histolytica by allicin, the active principle of garlic extract (Allium sativum). J Infect Dis, 156(1), 243–244CrossRefGoogle Scholar
Moreno, S. N., Mason, R. P., Muniz, R. P., Cruz, F. S. & Docampo, R. (1983). Generation of free radicals from metronidazole and other nitroimidazoles by Tritrichomonas foetus. J Biol Chem, 258(7), 4051–4054Google ScholarPubMed
Muller, M. (1986). Reductive activation of nitroimidazoles in anaerobic microorganisms. Biochem Pharmacol, 35(1), 37–41CrossRefGoogle ScholarPubMed
Muller, M. (1988). Energy metabolism of protozoa without mitochondria. Annu Rev Microbiol, 42, 465–488CrossRefGoogle ScholarPubMed
Muller, M. (1993). The hydrogenosome. J Gen Microbiology, 139, 2879–2889CrossRefGoogle ScholarPubMed
Muller, M., Lossick, J. G. & Gorrell, T. E. (1988). In vitro susceptibility of Trichomonas vaginalis to metronidazole and treatment outcome in vaginal trichomoniasis. Sex Transm Dis, 15(1), 17–24CrossRefGoogle ScholarPubMed
Paget, T. A., Raynor, M. H., Shipp, D. W. & Lloyd, D. (1990). Giardia lamblia produces alanine anaerobically but not in the presence of oxygen. Mol Biochem Parasitol, 42(1), 63–67CrossRefGoogle Scholar
Payne, M. J., Chapman, A. & Cammack, R. (1993). Evidence for an [Fe]-type hydrogenase in the parasitic protozoan Trichomonas vaginalis. FEBS Lett, 317(1–2), 101–104CrossRefGoogle Scholar
Peng, Z. Y., Mansour, J. M., Araujo, F., Ju, J. Y., McKenna, C. E. & Mansour, T. E. (1995). Some phosphonic acid analogs as inhibitors of pyrophosphate-dependent phosphofructokinase, a novel target in Toxoplasma gondii. Biochem Pharmacol, 49(1), 105–113CrossRefGoogle ScholarPubMed
Que, X. & Reed, S. L. (2000). Cysteine proteinases and the pathogenesis of amebiasis. Clin Microbiol Rev, 13(2), 196–206CrossRefGoogle ScholarPubMed
Quon, D. V., d'Oliveira, C. E. & Johnson, P. J. (1992). Reduced transcription of the ferredoxin gene in metronidazole-resistant Trichomonas vaginalis. Proc Natl Acad Sci USA, 89(10), 4402–4406CrossRefGoogle ScholarPubMed
Reed, S., Bouvier, J., Pollack, A. S., Engel, J. C., Brown, M., Hirata, K., Que, X., Eakin, A., Hagblom, P., Gillin, F.et al. (1993). Cloning of a virulence factor of Entamoeba histolytica. Pathogenic strains possess a unique cysteine proteinase gene. J Clin Invest, 91(4), 1532–1540CrossRefGoogle ScholarPubMed
Reeves, R. E. (1984). Metabolism of Entamoeba histolytica Schaudinn, 1903. Adv Parasitol, 23, 105–142CrossRefGoogle ScholarPubMed
Reeves, R. E. & Guthrie, J. D. (1975). Acetate kinase (pyrophosphate). A fourth pyrophosphate-dependent kinase from Entamoeba histolytica. Biochem Biophys Res Commun, 66(4), 1389–1395CrossRefGoogle ScholarPubMed
Reeves, R. E., Menzies, R. A. & Hsu, D. S. (1968). The pyruvate-phosphate dikinase reaction. The fate of phosphate and the equilibrium. J Biol Chem, 243(20), 5486–5491Google ScholarPubMed
Rodriguez, M., Hidalgo, M., Sanchez, T. & Orozco, E. (1996). Cloning and characterization of the Entamoeba histolytica pyruvate:ferredoxin osidoreductase gene. Mol Biochem Parasitol, 78, 273–277CrossRefGoogle ScholarPubMed
Rosenthal, P. J. (1999). Proteases of protozoan parasites. Adv Parasitol, 43, 105–159CrossRefGoogle ScholarPubMed
Saavedra-Lira, E., Ramirez-Silva, L. & Perez-Montfort, R. (1998). Expression and characterization of recombinant pyruvate phosphate dikinase from Entamoeba histolytica. Biochim Biophys Acta, 1382(1), 47–54CrossRefGoogle ScholarPubMed
Samarawickrema, N. A., Brown, D. M., Upcroft, J. A., Thammapalerd, N. & Upcroft, P. (1997). Involvement of superoxide dismutase and pyruvate:ferredoxin oxidoreductase in mechanisms of metronidazole resistance in Entamoeba histolytica. J Antimicrob Chemother, 40(6), 833–840CrossRefGoogle ScholarPubMed
Schofield, P. J., Edwards, M. R., Matthews, J. & Wilson, J. R. (1992). The pathway of arginine catabolism in Giardia intestinalis. Mol Biochem Parasitol, 51(1), 29–36CrossRefGoogle ScholarPubMed
Schroder, E. & Ponting, C. P. (1998). Evidence that peroxiredoxins are novel members of the thioredoxin fold superfamily. Protein Sci, 7(11), 2465–2468CrossRefGoogle ScholarPubMed
Sobel, J. D., Nagappan, V. & Nyirjesy, P. (1999). Metronidazole-resistant vaginal trichomoniasis – An emerging problem. N Engl J Med, 341(4), 292–293 [letter]CrossRefGoogle ScholarPubMed
Stanley, S. L. Jr., Zhang, T., Rubin, D. & Li, E. (1995). Role of the Entamoeba histolytica cysteine proteinase in amebic liver abscess formation in severe combined immunodeficient mice. Infect Immun, 63(4), 1587–1590Google ScholarPubMed
Strickland, G. T. (1991). Infections of the blood and reticuloendothelial system. In Hunter's Tropical Medicine (7th ed.). Philadelphia: Saunders
Townson, S. M., Upcroft, J. A. & Upcroft, P. (1996). Characterisation and purification of pyruvate:ferredoxin oxidoreductase from Giardia duodenalis. Mol Biochem Parasitol, 79(2), 183–193CrossRefGoogle ScholarPubMed
Upcroft, J. & Upcroft, P. (1993). Drug resistance and Giardia. Parasitol Today, 9, 187–190CrossRefGoogle ScholarPubMed
Volz, K. W., Krause, K. L. & Lipscomb, W. N. (1986). The binding of N-(phosphonacetyl)-L-aspartate to aspartate carbamoyltransferase of Escherichia coli. Biochem Biophys Res Commun, 136(2), 822–826CrossRefGoogle ScholarPubMed
Ward, W., Alvarado, L., Rawlings, N. D., Engel, J. C., Franklin, C. & McKerrow, J. H. (1997). A primitive enzyme for a primitive cell: The protease required for excystation of Giardia. Cell, 89(3), 437–444CrossRefGoogle ScholarPubMed
Wassmann, C., Hellberg, A., Tannich, E. & Bruchhaus, I. (1999). Metronidazole resistance in the protozoan parasite Entamoeba histolytica is associated with increased expression of iron-containing superoxide dismutase and peroxiredoxin and decreased expression of ferredoxin 1 and flavin reductase. J Biol Chem, 274(37), 26051–26056CrossRefGoogle ScholarPubMed
Williams, A. G. & Coombs, G. H. (1995). Multiple protease activities in Giardia intestinalis trophozoites. Int J Parasitol, 25(7), 771–778CrossRefGoogle ScholarPubMed
Williams, K. P., Leadlay, P. F. & Lowe, P. N. (1990). Inhibition of pyruvate:ferredoxin oxidoreductase from Trichomonas vaginalis by pyruvate and its analogues. Comparison with the pyruvate decarboxylase component of the pyruvate dehydrogenase complex. Biochem J, 268(1), 69–75CrossRefGoogle ScholarPubMed
Yang, W., Li, E., Kairong, T. & Stanley, S. L. Jr. (1994). Entamoeba histolytica has an alcohol dehydrogenase homologous to the multifunctional adhE gene product of Escherichia coli. Mol Biochem Parasitol, 64(2), 253–260CrossRefGoogle ScholarPubMed
Yong, T. S., Li, E., Clark, D. & Stanley, S. L. Jr. (1996). Complementation of an Escherichia coli adhE mutant by the Entamoeba histolytica EhADH2 gene provides a method for the identification of new antiamebic drugs. Proc Natl Acad Sci USA, 93(13), 6464–6469CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×