Advertisement

Arginase in Leishmania

  • Maria Fernanda Laranjeira da Silva
  • Lucile Maria Floeter-WinterEmail author
Part of the Subcellular Biochemistry book series (SCBI, volume 74)

Abstract

The presence of different sets of several enzymes that participate in the Krebs-Henseleit cycle has been used to identify several genera of trypanosomatids. One of these enzymes is arginase (L-arginine amidinohydrolase, E.C. 3.5.3.1), a metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. Arginase activity has been detected in Leishmania, Crithidia and Leptomonas but not in Trypanosoma, Herpetomonas or Phytomonas. The ureotelic behavior of some trypanosomatids is not due to urea excretion but to the production of ornithine to supply the polyamine pathway, which is essential for replication. Leishmania is found inside macrophages in the mammalian host and to live in these cells, the parasite must escape from several microbicidal mechanisms, such as nitric oxide (NO) production mediated by inducible nitric oxide synthase (iNOS). Since arginase and iNOS use the L-arginine as substrate, the amount of this amino acid available for both pathways is critical for parasite replication. In both promastigotes and amastigotes, arginase is located in the glycosome indicating that arginine trafficking in the cell is used to provide the optimal concentration of substrate for arginase. Arginine uptake by the parasite is also important in supplying the arginase substrate. Leishmania responds to arginine starvation by increasing the amino acid uptake. In addition to the external supply, the internal L-arginine pool also governs the uptake of this amino acid, and the size of this internal pool is modulated by arginase activity. Thus, arginine uptake and arginase activity are important in establishing and maintaining Leishmania infection.

Keywords

Nitric Oxide Urea Cycle Arginase Activity Leishmania Parasite Leishmania Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

AD

Arginine deiminase

AGM

Agmatinase

ARG

Arginase

ASL

Argininosuccinate lyase

ASS

Argininosuccinate synthetase

CAT

Cationic amino acid transporter

CH

Citrulline hydrolase

CPS1

Carbamoyl phosphate synthetase

EGFP

Enhanced green fluorescent protein

eNOS

Endothelial nitric oxide synthase

IFNγ

Interferon gamma

IL

Interleukin

iNOS

Inducible nitric oxide synthase

LOHA

Nω-hydroxy-L-arginine

LPG

Lipophosphoglycan

nNOS

Neuronal nitric oxide synthase

NO

Nitric oxide

OCT

Ornithine carbamoyltransferase

ORF

Open reading frame

PEX

Peroxin

PST1

Peroxisomal targeting signal type 1

PV

Parasitophorous vacuole

SSU rRNA

Small subunit ribosomal RNA

UTR

Untranslated region

Notes

Acknowledgments

 The authors received support from FAPESP and CNPq.

References

  1. Abbas AK, Lichtman AH (2007) Cellular and molecular immunology. Saunders Elsevier, PhiladelphiaGoogle Scholar
  2. Alexander J, Bryson K (2005) T helper (h)1/Th2 and Leishmania: paradox rather than paradigm. Immunol Lett 99(1):17–23PubMedCrossRefGoogle Scholar
  3. Batistoti M, Cavazzana M Jr, Serrano MG et al (2001) Genetic variability of trypanosomatids isolated from phytophagous hemiptera defined by morphological, biochemical, and molecular taxonomic markers. J Parasitol 87(6):1335–1341PubMedGoogle Scholar
  4. Berriman M, Ghedin E, Hertz-Fowler C et al (2005) The genome of the African trypanosome Trypanosoma brucei. Science 309(5733):416–422PubMedCrossRefGoogle Scholar
  5. Bogdan C, Rollinghoff M (1999) How do protozoan parasites survive inside macrophages? Parasitol Today 15(1):22–28PubMedCrossRefGoogle Scholar
  6. Boucher JL, Moali C, Tenu JP (1999) Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell Mol Life Sci 55(8–9):1015–1028PubMedCrossRefGoogle Scholar
  7. Briones MR, Nelson K, Beverley SM et al (1992) Leishmania tarentolae taxonomic relatedness inferred from phylogenetic analysis of the small subunit ribosomal RNA gene. Mol Biochem Parasitol 53(1–2):121–127PubMedCrossRefGoogle Scholar
  8. Calegari-Silva TC, Pereira RM, De-Melo LD et al (2009) NF-kappaB-mediated repression of iNOS expression in Leishmania amazonensis macrophage infection. Immunol Lett 127(1):19–26PubMedCrossRefGoogle Scholar
  9. Camargo EP (1979) Enzimas do ciclo ornitina-arginina em tripanosomatídeos: significado fisiológico e valor taxonômico. University of Sao Paulo, Sao PauloGoogle Scholar
  10. Camargo EP (1999) Phytomonas and other trypanosomatid parasites of plants and fruit. Adv Parasitol 42:29–112PubMedCrossRefGoogle Scholar
  11. Camargo EP, Coelho JA, Moraes G et al (1978) Trypanosoma spp., Leishmania spp. and Leptomonas spp.: enzymes of ornithine-arginine metabolism. Exp Parasitol 46(2):141–144PubMedCrossRefGoogle Scholar
  12. Camargo EP, Sbravate C, Teixeira MM et al (1992) Ribosomal DNA restriction analysis and synthetic oligonucleotide probing in the identification of genera of lower trypanosomatids. J Parasitol 78(1):40–48PubMedCrossRefGoogle Scholar
  13. Castilho-Martins EA, Laranjeira da Silva MF, Dos Santos MG et al (2011) Axenic Leishmania amazonensis promastigotes sense both the external and internal arginine pool distinctly regulating the two transporter-coding genes. PLoS One 6(11):e27818PubMedCrossRefGoogle Scholar
  14. Closs EI, Boissel JP, Habermeier A et al (2006) Structure and function of cationic amino acid transporters (CATs). J Membr Biol 213(2):67–77PubMedCrossRefGoogle Scholar
  15. Corraliza IM, Soler G, Eichmann K et al (1995) Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages. Biochem Biophys Res Commun 206(2):667–673PubMedCrossRefGoogle Scholar
  16. Cunningham AC (2002) Parasitic adaptive mechanisms in infection by leishmania. Exp Mol Pathol 72(2):132–141PubMedCrossRefGoogle Scholar
  17. da Silva ER, Castilho TM, Pioker FC et al (2002) Genomic organisation and transcription characterisation of the gene encoding Leishmania (Leishmania) amazonensis arginase and its protein structure prediction. Int J Parasitol 32(6):727–737PubMedCrossRefGoogle Scholar
  18. da Silva ER, da Silva MF, Fischer H et al (2008) Biochemical and biophysical properties of a highly active recombinant arginase from Leishmania (Leishmania) amazonensis and subcellular localization of native enzyme. Mol Biochem Parasitol 159(2):104–111PubMedCrossRefGoogle Scholar
  19. da Silva ER, Maquiaveli Cdo C, Magalhaes PP (2012a) The leishmanicidal flavonols quercetin and quercitrin target Leishmania (Leishmania) amazonensis arginase. Exp Parasitol 130(3):183–188PubMedCrossRefGoogle Scholar
  20. da Silva MF, Zampieri RA, Muxel SM et al (2012b) Leishmania amazonensis arginase compartmentalization in the glycosome is important for parasite infectivity. PLoS One 7(3):e34022PubMedCrossRefGoogle Scholar
  21. Descoteaux A, Turco SJ (1999) Glycoconjugates in Leishmania infectivity. Biochim Biophys Acta 1455(2–3):341–352PubMedGoogle Scholar
  22. Di Costanzo L, Sabio G, Mora A et al (2005) Crystal structure of human arginase I at 1.29-A resolution and exploration of inhibition in the immune response. Proc Natl Acad Sci USA 102(37):13058–13063PubMedCrossRefGoogle Scholar
  23. El-Sayed NM, Myler PJ, Bartholomeu DC et al (2005) The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 309(5733):409–415PubMedCrossRefGoogle Scholar
  24. Gaur U, Roberts SC, Dalvi RP et al (2007) An effect of parasite-encoded arginase on the outcome of murine cutaneous leishmaniasis. J Immunol 179(12):8446–8453PubMedGoogle Scholar
  25. Grody WW, Dizikes GJ, Cederbaum SD (1987) Human arginase isozymes. Isozymes Curr Top Biol Med Res 13:181–214PubMedGoogle Scholar
  26. Guerra-Giraldez C, Quijada L, Clayton CE (2002) Compartmentation of enzymes in a microbody, the glycosome, is essential in Trypanosoma brucei. J Cell Sci 115(Pt 13):2651–2658PubMedGoogle Scholar
  27. Haanstra JR, van Tuijl A, Kessler P et al (2008) Compartmentation prevents a lethal turbo-explosion of glycolysis in trypanosomes. Proc Natl Acad Sci U S A 105(46):17718–17723PubMedCrossRefGoogle Scholar
  28. Hart DT, Baudhuin P, Opperdoes FR et al (1987) Biogenesis of the glycosome in Trypanosoma brucei: the synthesis, translocation and turnover of glycosomal polypeptides. EMBO J 6(5):1403–1411PubMedGoogle Scholar
  29. Herdin SG (1895) Eine Methode das Lysin zu isoliren, nebst einigen Bemerkungen uber das Lysatinin. Z Physiol Chem 21:297–305CrossRefGoogle Scholar
  30. Hibbs JB Jr, Taintor RR, Vavrin Z (1987) Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science 235(4787):473–476PubMedCrossRefGoogle Scholar
  31. Hirshfield IN, Rosenfeld HJ, Leifer Z et al (1970) Isolation and characterization of a mutant of Escherichia coli blocked in the synthesis of putrescine. J Bacteriol 101(3):725–730PubMedGoogle Scholar
  32. Hrabak A, Bajor T, Temesi A et al (1996) The inhibitory effect of nitrite, a stable product of nitric oxide (NO) formation, on arginase. FEBS Lett 390(2):203–206PubMedCrossRefGoogle Scholar
  33. Iniesta V, Gomez-Nieto LC, Corraliza I (2001) The inhibition of arginase by N(omega)-hydroxy-l-arginine controls the growth of Leishmania inside macrophages. J Exp Med 193(6):777–784PubMedCrossRefGoogle Scholar
  34. Iniesta V, Carcelen J, Molano I et al (2005) Arginase I induction during Leishmania major infection mediates the development of disease. Infect Immun 73(9):6085–6090PubMedCrossRefGoogle Scholar
  35. Jenkinson CP, Grody WW, Cederbaum SD (1996) Comparative properties of arginases. Comp Biochem Physiol B Biochem Mol Biol 114(1):107–132PubMedCrossRefGoogle Scholar
  36. Kandpal M, Fouce RB, Pal A et al (1995) Kinetics and molecular characteristics of arginine transport by Leishmania donovani promastigotes. Mol Biochem Parasitol 71(2):193–201PubMedCrossRefGoogle Scholar
  37. Krazy H, Michels PA (2006) Identification and characterization of three peroxins – PEX6, PEX10 and PEX12 – involved in glycosome biogenesis in Trypanosoma brucei. Biochim Biophys Acta 1763(1):6–17PubMedCrossRefGoogle Scholar
  38. Krebs HA, Henseleit K (1932) Studies on urea formation in the animal organism. Z Physiol Chem 210:33–66CrossRefGoogle Scholar
  39. Kropf P, Fuentes JM, Fahnrich E et al (2005) Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo. FASEB J 19(8):1000–1002Google Scholar
  40. Manikandan K, Pal D, Ramakumar S et al (2008) Functionally important segments in proteins dissected using gene ontology and geometric clustering of peptide fragments. Genome Biol 9(3):R52PubMedCrossRefGoogle Scholar
  41. Moyersoen J, Choe J, Kumar A et al (2003) Characterization of Trypanosoma brucei PEX14 and its role in the import of glycosomal matrix proteins. Eur J Biochem 270(9):2059–2067PubMedCrossRefGoogle Scholar
  42. Muleme HM, Reguera RM, Berard A et al (2009) Infection with arginase-deficient Leishmania major reveals a parasite number-dependent and cytokine-independent regulation of host cellular arginase activity and disease pathogenesis. J Immunol 183(12):8068–8076PubMedCrossRefGoogle Scholar
  43. Munder M, Eichmann K, Modolell M (1998) Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. J Immunol 160(11):5347–5354PubMedGoogle Scholar
  44. Opperdoes FR (1987) Compartmentation of carbohydrate metabolism in trypanosomes. Annu Rev Microbiol 41:127–151PubMedCrossRefGoogle Scholar
  45. Opperdoes FR, Szikora JP (2006) In silico prediction of the glycosomal enzymes of Leishmania major and trypanosomes. Mol Biochem Parasitol 147(2):193–206PubMedCrossRefGoogle Scholar
  46. Qadoumi M, Becker I et al (2002) Expression of inducible nitric oxide synthase in skin lesions of patients with American cutaneous leishmaniasis. Infect Immun 70(8):4638–4642PubMedCrossRefGoogle Scholar
  47. Reczkowski RS, Ash DE (1992) EPR evidence for binuclear Mn(II) centers in rat liver arginase. J Am Chem Soc 114:10992–10994CrossRefGoogle Scholar
  48. Reguera RM, Balana-Fouce R, Showalter M et al (2009) Leishmania major lacking arginase (ARG) are auxotrophic for polyamines but retain infectivity to susceptible BALB/c mice. Mol Biochem Parasitol 165(1):48–56PubMedCrossRefGoogle Scholar
  49. Rey L (1992) Bases da parasitologia médica. Guanabara Koogan, Rio de JaneiroGoogle Scholar
  50. Roberts SC, Tancer MJ, Polinsky MR et al (2004) Arginase plays a pivotal role in polyamine precursor metabolism in Leishmania. Characterization of gene deletion mutants. J Biol Chem 279(22):23668–23678PubMedCrossRefGoogle Scholar
  51. Sacks DL, Pimenta PF et al (1995) Stage-specific binding of Leishmania donovani to the sand fly vector midgut is regulated by conformational changes in the abundant surface lipophosphoglycan. J Exp Med 181(2):685–697PubMedCrossRefGoogle Scholar
  52. Sastre M, Galea E, Feinstein D et al (1998) Metabolism of agmatine in macrophages: modulation by lipopolysaccharide and inhibitory cytokines. Biochem J 330(Pt 3):1405–1409PubMedGoogle Scholar
  53. Satishchandran C, Boyle SM (1986) Purification and properties of agmatine ureohydrolyase, a putrescine biosynthetic enzyme in Escherichia coli. J Bacteriol 165(3):843–848PubMedGoogle Scholar
  54. Schulze E, Steiger E (1886) Ueber das Arginin. Z Physiol Chem 11:43–65Google Scholar
  55. Shaked-Mishan P, Suter-Grotemeyer M, Yoel-Almagor T et al (2006) A novel high-affinity arginine transporter from the human parasitic protozoan Leishmania donovani. Mol Microbiol 60(1):30–38PubMedCrossRefGoogle Scholar
  56. Sommer JM, Bradley PJ, Wang CC et al (1996) Biogenesis of specialized organelles: glycosomes and hydrogenosomes. In: Smith DF, Parsons M (eds) Molecular biology of parasitic protozoa. IRL Press at Oxford University Press, New YorkGoogle Scholar
  57. Tamura K, Nei M (1993) Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. Mol Biol Evol 10(3):512–526PubMedGoogle Scholar
  58. Tamura K, Peterson D, Peterson N et al (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28(10):2731–2739PubMedCrossRefGoogle Scholar
  59. Tuon FF, Amato VS, Bacha HA et al (2008) Toll-like receptors and leishmaniasis. Infect Immun 76(3):866–872PubMedCrossRefGoogle Scholar
  60. Uribe E, Salas M, Enriquez S et al (2007) Cloning and functional expression of a rodent brain cDNA encoding a novel protein with agmatinase activity, but not belonging to the arginase family. Arch Biochem Biophys 461(1):146–150PubMedCrossRefGoogle Scholar
  61. Visigalli R, Bussolati O, Sala R et al (2004) The stimulation of arginine transport by TNFalpha in human endothelial cells depends on NF-kappaB activation. Biochim Biophys Acta 1664(1):45–52PubMedCrossRefGoogle Scholar
  62. Wanasen N, Soong L (2008) L-arginine metabolism and its impact on host immunity against Leishmania infection. Immunol Res 41(1):15–25PubMedCrossRefGoogle Scholar
  63. Wanasen N, MacLeod CL, Ellies LG et al (2007) L-arginine and cationic amino acid transporter 2B regulate growth and survival of Leishmania amazonensis amastigotes in macrophages. Infect Immun 75(6):2802–2810PubMedCrossRefGoogle Scholar
  64. Wang WW, Jenkinson CP, Griscavage JM et al (1995) Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide. Biochem Biophys Res Commun 210(3):1009–1016PubMedCrossRefGoogle Scholar
  65. Wu G, Morris SM Jr (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336(Pt 1):1–17PubMedGoogle Scholar
  66. Yeramian A, Martin L, Arpa L et al (2006) Macrophages require distinct arginine catabolism and transport systems for proliferation and for activation. Eur J Immunol 36(6):1516–1526PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Maria Fernanda Laranjeira da Silva
    • 1
  • Lucile Maria Floeter-Winter
    • 1
    Email author
  1. 1.Departamento de Fisiologia – Instituto de BiociênciasUniversidade de São PauloSão PauloBrazil

Personalised recommendations