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Central carbon metabolism of Leishmania parasites

Published online by Cambridge University Press:  17 February 2010

ELEANOR C. SAUNDERS
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
DAVID P. DE SOUZA
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
THOMAS NADERER
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
MARIJKE F. SERNEE
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
JULIE E. RALTON
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
MARIA A. DOYLE
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
JAMES I. MACRAE
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
JENNY L. CHAMBERS
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
JOANNE HENG
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
AMSHA NAHID
Affiliation:
Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
VLADIMIR A. LIKIC
Affiliation:
Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
MALCOLM J. MCCONVILLE*
Affiliation:
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Rd, Parkville, 3010, Victoria, Australia
*
*Corresponding author: Malcolm McConville. Tel: 61-3-8344 2342. Email: malcolmm@unimelb.edu.au

Summary

Leishmania spp. are sandfly-transmitted protozoa parasites that cause a spectrum of diseases in humans. Many enzymes involved in Leishmania central carbon metabolism differ from their equivalents in the mammalian host and are potential drug targets. In this review we summarize recent advances in our understanding of Leishmania central carbon metabolism, focusing on pathways of carbon utilization that are required for growth and pathogenesis in the mammalian host. While Leishmania central carbon metabolism shares many features in common with other pathogenic trypanosomatids, significant differences are also apparent. Leishmania parasites are also unusual in constitutively expressing most core metabolic pathways throughout their life cycle, a feature that may allow these parasites to exploit a range of different carbon sources (primarily sugars and amino acids) rapidly in both the insect vector and vertebrate host. Indeed, recent gene deletion studies suggest that mammal-infective stages are dependent on multiple carbon sources in vivo. The application of metabolomic approaches, outlined here, are likely to be important in defining aspects of central carbon metabolism that are essential at different stages of mammalian host infection.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2010

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References

REFERENCES

Akerman, M., Shaked-Mishan, P., Mazareb, S., Volpin, H. and Zilberstein, D. (2004). Novel motifs in amino acid permease genes from Leishmania. Biochemical and Biophysics Research Communications 325, 353366.CrossRefGoogle ScholarPubMed
Besteiro, S., Williams, R. A., Coombs, G. H. and Mottram, J. C. (2007). Protein turnover and differentiation in Leishmania. International Journal for Parasitology 37, 10631075.CrossRefGoogle ScholarPubMed
Bringaud, F., Riviere, L. and Coustou, V. (2006). Energy metabolism of trypanosomatids: adaptation to available carbon sources. Molecular and Biochemical Parasitology 149, 19.CrossRefGoogle ScholarPubMed
Bryson, K., Besteiro, S., McGachy, H. A., Coombs, G. H., Mottram, J. C. and Alexander, J. (2009). Overexpression of the natural inhibitor of cysteine peptidases in Leishmania mexicana leads to reduced virulence and a Th1 response. Infection and Immunity 77, 29712978.CrossRefGoogle Scholar
Burchmore, R. J., Rodriguez-Contreras, D., McBride, K., Merkel, P., Barrett, M. P., Modi, G., Sacks, D. and Landfear, S. M. (2003). Genetic characterization of glucose transporter function in Leishmania mexicana. Proceedings of the National Academy of Sciences, USA 100, 39013906.CrossRefGoogle ScholarPubMed
Chavali, A. K., Whittemore, J. D., Eddy, J. A., Williams, K. T. and Papin, J. A. (2008). Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major. Molecular Systems Biology 4, 177.CrossRefGoogle ScholarPubMed
Cohen-Freue, G., Holzer, T. R., Forney, J. D. and McMaster, W. R. (2007). Global gene expression in Leishmania. International Journal for Parasitology 37, 10771086.CrossRefGoogle ScholarPubMed
Coustou, V., Besteiro, S., Riviere, L., Biran, M., Biteau, N., Franconi, J. M., Boshart, M., Baltz, T. and Bringaud, F. (2005). A mitochondrial NADH-dependent fumarate reductase involved in the production of succinate excreted by procyclic Trypanosoma brucei. Journal of Biological Chemistry 280, 1655916570.CrossRefGoogle ScholarPubMed
Coustou, V., Biran, M., Breton, M., Guegan, F., Riviere, L., Plazolles, N., Nolan, D., Barrett, M. P., Franconi, J. M. and Bringaud, F. (2008). Glucose-induced remodeling of intermediary and energy metabolism in procyclic Trypanosoma brucei. Journal of Biological Chemistry 283, 1634216354.CrossRefGoogle ScholarPubMed
Croft, S. L. and Coombs, G. H. (2003). Leishmaniasis – current chemotherapy and recent advances in the search for novel drugs. Trends in Parasitology 19, 502508.CrossRefGoogle ScholarPubMed
De Souza, D. P., Saunders, E. C., McConville, M. J. and Likic, V. A. (2006). Progressive peak clustering in GC-MS metabolomic experiments applied to Leishmania parasites. Bioinformatics 22, 13911396.CrossRefGoogle ScholarPubMed
Doyle, M. A., MacRae, J. I., De Souza, D. P., Saunders, E. C., McConville, M. J. and Likic, V. A. (2009). LeishCyc: a biochemical pathways database for Leishmania major. BMC Systems Biology 3, 57.CrossRefGoogle ScholarPubMed
Fan, W., Kraus, P. R., Boily, M. J. and Heitman, J. (2005). Cryptococcus neoformans gene expression during murine macrophage infection. Eukaryotic Cell 4, 14201433.CrossRefGoogle ScholarPubMed
Feng, X., Rodriguez-Contreras, D., Buffalo, C., Bouwer, H. G., Kruvand, E., Beverley, S. M. and Landfear, S. M. (2009). Amplification of an alternate transporter gene suppresses the avirulent phenotype of glucose transporter null mutants in Leishmania mexicana. Molecular Microbiology 71, 369381.CrossRefGoogle ScholarPubMed
Garami, A. and Ilg, T. (2001 a). Disruption of mannose activation in Leishmania mexicana: GDP-mannose pyrophosphorylase is required for virulence, but not for viability. EMBO Journal 20, 36573666.CrossRefGoogle Scholar
Garami, A. and Ilg, T. (2001 b). The role of phosphomannose isomerase in Leishmania mexicana glycoconjugate synthesis and virulence. Journal of Biological Chemistry 276, 65666575.CrossRefGoogle ScholarPubMed
Gaur, U., Roberts, S. C., Dalvi, R. P., Corraliza, I., Ullman, B. and Wilson, M. E. (2007). An effect of parasite-encoded arginase on the outcome of murine cutaneous leishmaniasis. Journal of Immunology 179, 84468453.CrossRefGoogle ScholarPubMed
Gorin, P. A., Previato, J. O., Mendonca-Previato, L. and Travassos, L. R. (1979). Structure of the D-mannan and D-arabino-D-galactan in Crithidia fasciculata: changes in proportion with age of culture. Journal of Protozoology 26, 473478.CrossRefGoogle ScholarPubMed
Guerra, D. G., Decottignies, A., Bakker, B. M. and Michels, P. A. (2006). The mitochondrial FAD-dependent glycerol-3-phosphate dehydrogenase of Trypanosomatidae and the glycosomal redox balance of insect stages of Trypanosoma brucei and Leishmania spp. Molecular and Biochemical Parasitology 149, 155169.CrossRefGoogle ScholarPubMed
Gupta, N., Goyal, N., Singha, U. K., Bhakuni, V., Roy, R. and Rastogi, A. K. (1999). Characterization of intracellular metabolites of axenic amastigotes of Leishmania donovani by 1H NMR spectroscopy. Acta Tropica 73, 121133.CrossRefGoogle Scholar
Hart, D. T. and Coombs, G. H. (1982). Leishmania mexicana: energy metabolism of amastigotes and promastigotes. Experimental Parasitology 54, 397409.CrossRefGoogle Scholar
Hellemond, J. J., Bakker, B. M. and Tielens, A. G. (2005). Energy metabolism and its compartmentation in Trypanosoma brucei. Advances in Microbial Physiology 50, 199226.CrossRefGoogle ScholarPubMed
Holzer, T. R., McMaster, W. R. and Forney, J. D. (2006). Expression profiling by whole-genome interspecies microarray hybridization reveals differential gene expression in procyclic promastigotes, lesion-derived amastigotes, and axenic amastigotes in Leishmania mexicana. Molecular and Biochemical Parasitology 146, 198218.CrossRefGoogle ScholarPubMed
Kropf, P., Fuentes, J. M., Fahnrich, E., Arpa, L., Herath, S., Weber, V., Soler, G., Celada, A., Modolell, M. and Muller, I. (2005). Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo. FASEB Journal 19, 10001002.CrossRefGoogle ScholarPubMed
Kuhn, D. and Wiese, M. (2005). LmxPK4, a mitogen-activated protein kinase kinase homologue of Leishmania mexicana with a potential role in parasite differentiation. Molecular Microbiology 56, 11691182.CrossRefGoogle ScholarPubMed
Lamour, N., Riviere, L., Coustou, V., Coombs, G. H., Barrett, M. P. and Bringaud, F. (2005). Proline metabolism in procyclic Trypanosoma brucei is down-regulated in the presence of glucose. Journal of Biological Chemistry 280, 1190211910.CrossRefGoogle ScholarPubMed
Landfear, S. M. (2008). Drugs and transporters in kinetoplastid protozoa. Advances in Experimental Medical Biology 625, 2232.Google ScholarPubMed
Maugeri, D. A., Cazzulo, J. J., Burchmore, R. J., Barrett, M. P. and Ogbunude, P. O. (2003). Pentose phosphate metabolism in Leishmania mexicana. Molecular and Biochemical Parasitology 130, 117125.CrossRefGoogle ScholarPubMed
McConville, M. J. and Blackwell, J. M. (1991). Developmental changes in the glycosylated phosphatidylinositols of Leishmania donovani. Characterization of the promastigote and amastigote glycolipids. Journal of Biological Chemistry 266, 1517015179.CrossRefGoogle ScholarPubMed
Mendonca-Previato, L., Gorin, P. A. and Previato, J. O. (1979). Investigations on polysaccharide components of cells of Herpetomonas samuelpessoai grown on various media. Biochemistry 18, 149154.CrossRefGoogle ScholarPubMed
Morales, M. A., Renaud, O., Faigle, W., Shorte, S. L. and Spath, G. F. (2007). Over-expression of Leishmania major MAP kinases reveals stage-specific induction of phosphotransferase activity. International Journal for Parasitology 37, 11871199.CrossRefGoogle ScholarPubMed
Morales, M. A., Watanabe, R., Laurent, C., Lenormand, P., Rousselle, J. C., Namane, A. and Spath, G. F. (2008). Phosphoproteomic analysis of Leishmania donovani pro- and amastigote stages. Proteomics 8, 350363.CrossRefGoogle ScholarPubMed
Naderer, T., Ellis, M. A., Sernee, M. F., De Souza, D. P., Curtis, J., Handman, E. and McConville, M. J. (2006). Virulence of Leishmania major in macrophages and mice requires the gluconeogenic enzyme fructose-1,6-bisphosphatase. Proceedings of the National Academy of Sciences, USA 103, 55025507.CrossRefGoogle ScholarPubMed
Naderer, T. and McConville, M. J. (2008). The Leishmania-macrophage interaction: a metabolic perspective. Cellular Microbiology 10, 301308.CrossRefGoogle ScholarPubMed
Oberhardt, M. A., Chavali, A. K. and Papin, J. A. (2009). Flux balance analysis: interrogating genome-scale metabolic networks. Methods in Molecular Biology 500, 6180.CrossRefGoogle ScholarPubMed
Opperdoes, F. and Coombs, G. H. (2007). Metabolism of Leishmania; proven and predicted. Trends in Parasitology 23, 149158.CrossRefGoogle ScholarPubMed
Paape, D., Lippuner, C., Schmid, M., Ackermann, R., Barrios-Llerena, M. E., Zimny-Arndt, U., Brinkmann, V., Arndt, B., Pleissner, K. P., Jungblut, P. R. et al. (2008). Transgenic, fluorescent Leishmania mexicana allow direct analysis of the proteome of intracellular amastigotes. Molecular and Cellular Proteomics 7, 16881701.CrossRefGoogle ScholarPubMed
Peacock, C. S., Seeger, K., Harris, D., Murphy, L., Ruiz, J. C., Quail, M. A., Peters, N., Adlem, E., Tivey, A., Aslett, M. et al. (2007). Comparative genomic analysis of three Leishmania species that cause diverse human disease. Nature Genetics 39, 839847.CrossRefGoogle ScholarPubMed
Peters, N. C., Egen, J. G., Secundino, N., Debrabant, A., Kimblin, N., Kamhawi, S., Lawyer, P., Fay, M. P., Germain, R. N. and Sacks, D. (2008). In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies. Science 321, 970974.CrossRefGoogle ScholarPubMed
Rainey, P. M. and MacKenzie, N. E. (1991). A carbon-13 nuclear magnetic resonance analysis of the products of glucose metabolism in Leishmania pifanoi amastigotes and promastigotes. Molecular and Biochemical Parasitology 45, 307315.CrossRefGoogle Scholar
Ralton, J. E., Naderer, T., Piraino, H. L., Bashtannyk, T. A., Callaghan, J. M. and McConville, M. J. (2003). Evidence that intracellular beta1-2 mannan is a virulence factor in Leishmania parasites. Journal of Biological Chemistry 278, 4075740763.CrossRefGoogle ScholarPubMed
Reguera, R. M., Balana-Fouce, R., Showalter, M., Hickerson, S. and Beverley, S. M. (2009). Leishmania major lacking arginase (ARG) are auxotrophic for polyamines but retain infectivity to susceptible BALB/c mice. Molecular and Biochemical Parasitology 165, 4856.CrossRefGoogle ScholarPubMed
Riviere, L., Moreau, P., Allmann, S., Hahn, M., Biran, M., Plazolles, N., Franconi, J. M., Boshart, M. and Bringaud, F. (2009). Acetate produced in the mitochondrion is the essential precursor for lipid biosynthesis in procyclic trypanosomes. Proceedings of the National Academy of Sciences, USA 106, 1269412699.CrossRefGoogle ScholarPubMed
Riviere, L., van Weelden, S. W., Glass, P., Vegh, P., Coustou, V., Biran, M., van Hellemond, J. J., Bringaud, F., Tielens, A. G. and Boshart, M. (2004). Acetyl:succinate CoA-transferase in procyclic Trypanosoma brucei. Gene identification and role in carbohydrate metabolism. Journal of Biological Chemistry 279, 4533745346.CrossRefGoogle ScholarPubMed
Robinson, M. D., De Souza, D. P., Keen, W. W., Saunders, E. C., McConville, M. J., Speed, T. P. and Likic, V. A. (2007). A dynamic programming approach for the alignment of signal peaks in multiple gas chromatography-mass spectrometry experiments. BMC Bioinformatics 8, 419.CrossRefGoogle ScholarPubMed
Rodriguez-Contreras, D., Feng, X., Keeney, K. M., Bouwer, H. G. and Landfear, S. M. (2007). Phenotypic characterization of a glucose transporter null mutant in Leishmania mexicana. Molecular and Biochemical Parasitology 153, 9–18.CrossRefGoogle ScholarPubMed
Rogers, S., Scheltema, R. A., Girolami, M. and Breitling, R. (2009). Probabilistic assignment of formulas to mass peaks in metabolomics experiments. Bioinformatics 25, 512518.CrossRefGoogle ScholarPubMed
Rosenzweig, D., Smith, D., Myler, P. J., Olafson, R. W. and Zilberstein, D. (2008). Post-translational modification of cellular proteins during Leishmania donovani differentiation. Proteomics 8, 18431850.CrossRefGoogle ScholarPubMed
Rosenzweig, D., Smith, D., Opperdoes, F., Stern, S., Olafson, R. W. and Zilberstein, D. (2007). Retooling Leishmania metabolism: from sand fly gut to human macrophage. FASEB Journal 22, 590602.CrossRefGoogle ScholarPubMed
Rubin-Bejerano, I., Fraser, I., Grisafi, P. and Fink, G. R. (2003). Phagocytosis by neutrophils induces an amino acid deprivation response in Saccharomyces cerevisiae and Candida albicans. Proceedings of the National Acadedmy of Sciences, USA 100, 1100711012.CrossRefGoogle ScholarPubMed
Scott, D. A., Hickerson, S. M., Vickers, T. J. and Beverley, S. M. (2008). The role of the mitochondrial glycine cleavage complex in the metabolism and virulence of the protozoan parasite Leishmania major. Journal of Biological Chemistry 283, 155165.CrossRefGoogle Scholar
Sernee, M. F., Ralton, J. E., Dinev, Z., Khairallah, G. N., O'Hair, R. A., Williams, S. J. and McConville, M. J. (2006). Leishmania beta-1,2-mannan is assembled on a mannose-cyclic phosphate primer. Proceedings of the National Academy of Sciences, USA 103, 94589463.CrossRefGoogle Scholar
Shaked-Mishan, P., Suter-Grotemeyer, M., Yoel-Almagor, T., Holland, N., Zilberstein, D. and Rentsch, D. (2006). A novel high-affinity arginine transporter from the human parasitic protozoan Leishmania donovani. Molecular Microbiology 60, 3038.CrossRefGoogle ScholarPubMed
Smith, D. F., Peacock, C. and Cruz, A. K. (2007). Comparative genomics; from geneotype to disease phenotype in the leishmaniases. International Journal for Parasitology 37, 11731186.CrossRefGoogle Scholar
Stuart, K., Brun, R., Croft, S., Fairlamb, A., Gurtler, R. E., McKerrow, J., Reed, S. and Tarleton, R. (2008). Kinetoplastids: related protozoan pathogens, different diseases. Journal of Clinical Investigation 118, 13011310.CrossRefGoogle ScholarPubMed
Tasker, M., Timms, M., Hendriks, E. and Matthews, K. (2001). Cytochrome oxidase subunit VI of Trypanosoma brucei is imported without a cleaved presequence and is developmentally regulated at both RNA and protein levels. Molecular Microbiology 39, 272285.CrossRefGoogle ScholarPubMed
Tielens, A. G. and van Hellemond, J. J. (2009). Surprising variety in energy metabolism within Trypanosomatidae. Trends in Parasitology 25, 482490.CrossRefGoogle ScholarPubMed
Van Hellemond, J. J. and Tielens, A. G. (1997 a). Inhibition of the respiratory chain results in a reversible metabolic arrest in Leishmania promastigotes. Molecular and Biochemical Parasitology 85, 135138.CrossRefGoogle Scholar
Van Hellemond, J. J. and Tielens, A. G. (1997 b). Inhibition of the respiratory chain results in a reversible metabolic arrest in Leishmania promastigotes. Molecular and Biochemical Parasitology 85, 135138.CrossRefGoogle Scholar
van Weelden, S. W., van Hellemond, J. J., Opperdoes, F. R. and Tielens, A. G. (2005). New functions for parts of the Krebs cycle in procyclic Trypanosoma brucei, a cycle not operating as a cycle. Journal of Biological Chemistry 280, 1245112460.CrossRefGoogle Scholar
Wiese, M. (1998). A mitogen-activated protein (MAP) kinase homologue of Leishmania mexicana is essential for parasite survival in the infected host. EMBO Journal 17, 26192628.CrossRefGoogle ScholarPubMed
Wiese, M. (2007). Leishmania MAP kinases – familiar proteins in an unusual context. International Journal for Parasitology 37, 10531062.CrossRefGoogle Scholar
Winter, G., Fuchs, M., McConville, M. J., Stierhof, Y. D. and Overath, P. (1994). Surface antigens of Leishmania mexicana amastigotes: characterization of glycoinositol phospholipids and a macrophage-derived glycosphingolipid. Journal of Cell Science 107, 24712482.CrossRefGoogle Scholar
Zamboni, N., Fendt, S. M., Ruhl, M. and Sauer, U. (2009). (13)C-based metabolic flux analysis. Nature Protocols 4, 878892.CrossRefGoogle ScholarPubMed
Zamboni, N. and Sauer, U. (2009). Novel biological insights through metabolomics and 13C-flux analysis. Current Opinion in Microbiology 12, 553558.CrossRefGoogle ScholarPubMed
Zhang, K., Hsu, F. F., Scott, D. A., Docampo, R., Turk, J. and Beverley, S. M. (2005). Leishmania salvage and remodelling of host sphingolipids in amastigote survival and acidocalcisome biogenesis. Molecular Microbiology 55, 15661578.CrossRefGoogle ScholarPubMed
Zikova, A., Schnaufer, A., Dalley, R. A., Panigrahi, A. K. and Stuart, K. D. (2009). The F(0)F(1)-ATP synthase complex contains novel subunits and is essential for procyclic Trypanosoma brucei. PLoS Pathogens 5, e1000436.CrossRefGoogle Scholar