Top

Published in:

01-03-2019 | Review Article

Dependence of Leishmania parasite on host derived ATP: an overview of extracellular nucleotide metabolism in parasite

Authors: Kashika Arora, Ambak Kumar Rai

Published in: Journal of Parasitic Diseases | Issue 1/2019

Abstract

The widespread role of ATP in humans has been characterized as a substrate for metabolism as well as other key processes occurring in the human system. Hence, the ATP pool may also be accessible to the invaders, including Leishmania donovani (a protozoan parasite), considering the fact that ATP is not scarce at the cellular location where the pathogen resides. The protozoan parasite survives in the human host by utilizing purines from its extracellular environment, due to its inability to synthesize purines de novo. The purines are accessible in the form of nucleoside triphosphates (NTPs), for example, adenosine (ADO) in the form of ATP molecules. These NTPs are processed by the ecto-nucleotidases in the transmembrane region of the parasite, which are then transported inside via nucleoside/nucleobase transporters belonging to the ENT family of transporters. Besides, the breakdown of NTPs by ecto-nucleotidases also yields inorganic phosphate (Pi) as by-product which is utilized by the parasite to maintain Pi homeostasis. These transporters have been characterized in protozoan parasites exhibiting homology in various species of Leishmania. Once inside the parasite, these purines (or their derivatives) are fluxed into purine metabolic pathways with the help of several cytosolic enzymes, prominently, adenosine deaminase, adenine amino hydrolase, phosphoribosyl transferases (APRT, HGPRT and XPRT) and adenosine kinase. This review outlines the predominant role of extracellular nucleotide metabolism and intracellular metabolic machinery in the containment of leishmanial infection. It also highlights the importance of inorganic phosphate transporter in relation to the purine transport.

Graphical abstract

Almeida-Amaral EED et al (2006) Leishmania amazonensis: characterization of an ecto-phosphatase activity. Exp Parasitol 114(4):334–340. https://doi.org/10.1016/j.exppara.2006.04.011 CrossRefPubMed

Al-Salabi MI, De Koning HP (2005) Purine nucleobase transport in amastigotes of Leishmania mexicana: involvement in allopurinol uptake. Antimicrob Agents Chemother. https://doi.org/10.1128/aac.49.9.3682-3689.2005 CrossRefPubMedPubMedCentral

Alvar J et al (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE. https://doi.org/10.1371/journal.pone.0035671 CrossRefPubMedPubMedCentral

Alzahrani KJH et al (2017) Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: implications for pyrimidine-based chemotherapy. Int J Parasitol Drugs Drug Resist. https://doi.org/10.1016/j.ijpddr.2017.04.003 CrossRefPubMedPubMedCentral

Andrade BB et al (2007) Role of sand fly saliva in human and experimental leishmaniasis: current insights. Scand J Immunol 66:122–127. https://doi.org/10.1111/j.1365-3083.2007.01964.x CrossRefPubMed

Ashutosh SS, Goyal N (2007) Molecular mechanisms of antimony resistance in Leishmania. J Med Microbiol 56(PART 2):143–153. https://doi.org/10.1099/jmm.0.46841-0 CrossRefPubMed

Baiocco P et al (2009) Molecular basis of antimony treatment in Leishmaniasis. J Med Chem 52:2603–2612. https://doi.org/10.1021/jm900185q CrossRefPubMed

Berg M et al (2010) Inhibitors of the purine salvage pathway: a valuable approach for antiprotozoal chemotherapy? Curr Med Chem. https://doi.org/10.2174/092986710791556023 CrossRefPubMed

Boitz JM, Ullman B (2006) A conditional mutant deficient in hypoxanthine-guanine phosphoribosyltransferase and xanthine phosphoribosyltransferase validates the purine salvage pathway of Leishmania donovani. J Biol Chem. https://doi.org/10.1074/jbc.m600188200 CrossRefPubMed

Boitz JM, Ullman B (2013) Adenine and adenosine salvage in Leishmania donovani. Mol Biochem Parasitol. https://doi.org/10.1016/j.molbiopara.2013.06.005 CrossRefPubMedPubMedCentral

Boitz JM, Strasser R et al (2012a) Adenine aminohydrolase from Leishmania donovani. Unique enzyme in parasite purine metabolism. J Biol Chem. https://doi.org/10.1074/jbc.m111.307884 CrossRefPubMedPubMedCentral

Boitz JM, Ullman B et al (2012b) Purine salvage in Leishmania: complex or simple by design? Trends Parasitol 28(8):345–352. https://doi.org/10.1016/j.pt.2012.05.005 CrossRefPubMedPubMedCentral

Brunschweiger A et al (2008) Selective nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) inhibitors: nucleotide mimetics derived from uridine-5′-carboxamide. J Med Chem. https://doi.org/10.1021/jm800175e CrossRefPubMedPubMedCentral

Cano-Soldado P, Pastor-Anglada M (2012) Transporters that translocate nucleosides and structural similar drugs: structural requirements for substrate recognition. Med Res Rev. https://doi.org/10.1002/med.20221 CrossRefPubMed

Carter NS et al (2000) Cloning of a novel inosine-guanosine transporter gene from Leishmania donovani by functional rescue of a transport-deficient mutant. J Biol Chem 275(27):20935–20941. https://doi.org/10.1074/jbc.M002418200 CrossRefPubMed

Carter NS, Landfear SM, Ullman B (2001) Nucleoside transporters of parasitic protozoa. Trends Parasitol 17(3):142–145. https://doi.org/10.1016/S1471-4922(00)01806-7 CrossRefPubMed

Carter NS et al (2010) Adaptive responses to purine starvation in Leishmania donovani. Mol Microbiol. https://doi.org/10.1111/j.1365-2958.2010.07327.x CrossRefPubMedPubMedCentral

Chawla B, Madhubala R (2010) Drug targets in Leishmania. J Parasit Dis. https://doi.org/10.1007/s12639-010-0006-3 CrossRefPubMedPubMedCentral

Côrtes DF et al (2010) Low and high-dose intradermal infection with Leishmania major and Leishmania amazonensis in C57BL/6 mice. Mem Inst Oswaldo Cruz. https://doi.org/10.1590/s0074-02762010000600002 CrossRefPubMed

Cosentino-Gomes D, Meyer-Fernandes JR (2011) Ecto-phosphatases in protozoan parasites: possible roles in nutrition, growth and ROS sensing. J Bioenerg Biomembr 43(1):89–92. https://doi.org/10.1007/s10863-011-9334-y CrossRefPubMed

Cummings HE et al (2012) Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis. Proc Natl Acad Sci. https://doi.org/10.1073/pnas.1110339109 CrossRefPubMed

Datta R et al (2005) Mutational analysis of the active-site residues crucial for catalytic activity of adenosine kinase from Leishmania donovani. Biochem J. https://doi.org/10.1042/bj20041733 CrossRefPubMedPubMedCentral

Dayakar A et al (2012) A rapid method to assess the stage differentiation in Leishmania donovani by flow cytometry. Exp Parasitol. https://doi.org/10.1016/j.exppara.2012.09.006 CrossRefPubMed

de Almeida Marques-da-Silva E et al (2008) Extracellular nucleotide metabolism in Leishmania: influence of adenosine in the establishment of infection. Microbes Infect. https://doi.org/10.1016/j.micinf.2008.04.016 CrossRefPubMed

de Souza Leite M et al (2007) Trypanosoma brucei brucei: biochemical characterization of ecto-nucleoside triphosphate diphosphohydrolase activities. Exp Parasitol. https://doi.org/10.1016/j.exppara.2006.09.002 CrossRefPubMed

de Souza MC et al (2010) The influence of ecto-nucleotidases on Leishmania amazonensis infection and immune response in C57B/6 mice. Acta Trop. https://doi.org/10.1016/j.actatropica.2010.04.007 CrossRefPubMed

Dick CF, Dos-Santos ALA, Meyer-Fernandes JR (2014) Inorganic phosphate uptake in unicellular eukaryotes. Biochim Biophys Acta Gen Subj. https://doi.org/10.1016/j.bbagen.2014.03.014 CrossRef

Dwyer KM et al (2007) CD39 and control of cellular immune responses. Purinergic Signal. https://doi.org/10.1007/s11302-006-9050-y CrossRefPubMedPubMedCentral

Eilers M et al (2000) Internal packing of helical membrane proteins. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.97.11.5796 CrossRefPubMedPubMedCentral

El Fadili K et al (2005) Role of the ABC transporter MRPA (PGPA) in antimony resistance in Leishmania infantum axenic and intracellular amastigotes. Antimicrob Agents Chemother. https://doi.org/10.1128/aac.49.5.1988-1993.2005 CrossRefPubMedPubMedCentral

Faleiro RJ et al (2014) Immune regulation during chronic visceral leishmaniasis. PLoS Negl Trop Dis. https://doi.org/10.1371/journal.pntd.0002914 CrossRefPubMedPubMedCentral

Fonseca FV et al (2006) Trypanosoma rangeli: characterization of a Mg-dependent ecto ATP-diphosphohydrolase activity. Exp Parasitol. https://doi.org/10.1016/j.exppara.2005.09.005 CrossRefPubMed

Freitas-Mesquita AL, Meyer-Fernandes JR (2014) Ecto-nucleotidases and ecto-phosphatases from Leishmania and Trypanosoma parasites. Sub-Cell Biochem. https://doi.org/10.1007/978-94-007-7305-9_10 CrossRef

Fukuda Y, Schuetz JD (2012) ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol. https://doi.org/10.1016/j.bcp.2011.12.042 CrossRefPubMedPubMedCentral

Galazka J et al (2006) Point mutations within the LdNT2 nucleoside transporter gene from Leishmania donovani confer drug resistance and transport deficiency. Int J Biochem Cell Biol. https://doi.org/10.1016/j.biocel.2005.12.016 CrossRefPubMed

García-Hernández R et al (2012) Leishmania donovani develops resistance to drug combinations. PLoS Negl Trop Dis. https://doi.org/10.1371/journal.pntd.0001974 CrossRefPubMedPubMedCentral

Giarola NLL et al (2014) Leishmania amazonensis: increase in ecto-ATPase activity and parasite burden of vinblastine-resistant protozoa. Exp Parasitol. https://doi.org/10.1016/j.exppara.2014.08.013 CrossRefPubMed

Guimarães-Costa AB et al (2014) 3′-nucleotidase/nuclease activity allows Leishmania parasites to escape killing by neutrophil extracellular traps. Infect Immun 82(4):1732–1740. https://doi.org/10.1128/IAI.01232-13 CrossRefPubMedPubMedCentral

Gupta S (2011) Visceral leishmaniasis: experimental models for drug discovery. Indian J Med Res 133:27–39PubMedPubMedCentral

Hunsucker SA, Mitchell BS, Spychala J (2005) The 5′-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacol Ther. https://doi.org/10.1016/j.pharmthera.2005.01.003 CrossRefPubMed

Kato H et al (2007) Identification and characterization of a salivary adenosine deaminase from the sand fly Phlebotomus duboscqi, the vector of Leishmania major in sub-Saharan Africa. J Exp Biol 210(Pt 5):733–740. https://doi.org/10.1242/jeb.001289 CrossRefPubMed

Landfear SM (2008) Drugs and transporters in kinetoplastid protozoa. Adv Exp Med Biol. https://doi.org/10.1007/978-0-387-77570-8_3 CrossRefPubMed

Landfear SM et al (2004) Nucleoside and nucleobase transporters in parasitic protozoa. Eukaryot Cell 3(2):245–254. https://doi.org/10.1128/ec.3.2.245 CrossRefPubMedPubMedCentral

Leite PM et al (2012) Ecto-nucleotidase activities of promastigotes from Leishmania (Viannia) braziliensis relates to parasite infectivity and disease clinical outcome. PLoS Negl Trop Dis 6(10):e1850. https://doi.org/10.1371/journal.pntd.0001850 CrossRefPubMedPubMedCentral

Leprohon P et al (2015) Drug resistance analysis by next generation sequencing in Leishmania. Int J Parasitol Drugs Drug Resist. https://doi.org/10.1016/j.ijpddr.2014.09.005 CrossRefPubMed

Liu W et al (2006) Functional characterization of nucleoside transporter gene replacements in Leishmania donovani. Mol Biochem Parasitol. https://doi.org/10.1016/j.molbiopara.2006.09.002 CrossRefPubMedPubMedCentral

Loeuillet C, Bañuls AL, Hide M (2016) Study of Leishmania pathogenesis in mice: experimental considerations. Paras Vectors. https://doi.org/10.1186/s13071-016-1413-9 CrossRef

Manzano JI, Castanys S (2013) A new ABC half-transporter in leishmania major is involved in resistance to antimony. Antimicrob Agents Chemother. https://doi.org/10.1128/aac.00211-13 CrossRefPubMedPubMedCentral

Martin JL et al (2014) Metabolic Reprogramming during Purine Stress in the Protozoan Pathogen Leishmania donovani. PLoS Pathog 10(2):e1003938. https://doi.org/10.1371/journal.ppat.1003938 CrossRefPubMedPubMedCentral

Maxwell MJ et al (2008) Proteomic analysis of the secretome of Leishmania donovani. Genome Biol. https://doi.org/10.1186/gb-2008-9-2-r35 CrossRef

Mondal S, Roy JJ, Bera T (2014) Generation of adenosine tri-phosphate in Leishmania donovani amastigote forms. Acta Parasitol 59(1):11–16. https://doi.org/10.2478/s11686-014-0203-9 CrossRefPubMed

Naderer T, Vince JE, McConville MJ (2004) Surface determinants of Leishmania parasites and their role in infectivity in the mammalian host. Curr Mol Med. https://doi.org/10.2174/1566524043360069 CrossRefPubMed

Ortiz D et al (2007) Molecular genetic analysis of purine nucleobase transport in Leishmania major. Mol Microbiol 64(5):1228–1243. https://doi.org/10.1111/j.1365-2958.2007.05730.x CrossRefPubMed

Ortiz D et al (2009) An acid-activated nucleobase transporter from Leishmania major. J Biol Chem 284(24):16164–16169. https://doi.org/10.1074/jbc.M109.006718 CrossRefPubMedPubMedCentral

Paes-Vieira L, Gomes-Vieira AL, Meyer-Fernandes JR (2018) NTPDase activities: possible roles on Leishmania spp infectivity and virulence. Cell Biol Int. https://doi.org/10.1002/cbin.10944 CrossRefPubMed

Paletta-Silva R et al (2011) Leishmania amazonensis: characterization of an ecto-3’-nucleotidase activity and its possible role in virulence. Exp Parasitol. https://doi.org/10.1016/j.exppara.2011.07.014 CrossRefPubMed

Paletta-Silva R et al (2012) Leishmania amazonensis: inhibition of 3′-nucleotidase activity by Cu²⁺ions. Exp Parasitol. https://doi.org/10.1016/j.exppara.2012.03.001 CrossRefPubMed

Parodi-talice ÂA (2001) ABC transporters in the protozoan parasite Leishmania. Int Microbiol 4:159–166. https://doi.org/10.1007/s10123-001-0031-2 CrossRefPubMed

Pereira-Neves A et al (2014) Tritrichomonas foetus: characterisation of ecto-phosphatase activities in the endoflagelar form and their possible participation on the parasite’s transformation and cytotoxicity. Exp Parasitol. https://doi.org/10.1016/j.exppara.2014.04.007 CrossRefPubMed

Peres-Sampaio CE et al (2008) Leishmania amazonensis: effects of heat shock on ecto-ATPase activity. Exp Parasitol. https://doi.org/10.1016/j.exppara.2008.01.003 CrossRefPubMed

Pinheiro CM et al (2006) Leishmania amazonensis: biological and biochemical characterization of ecto-nucleoside triphosphate diphosphohydrolase activities. Exp Parasitol 114(1):16–25. https://doi.org/10.1016/j.exppara.2006.02.007 CrossRefPubMed

Podgorska M, Kocbuch K, Pawelczyk T (2005) Recent advances in studies on biochemical and structural properties of equilibrative and concentrative nucleoside transporters. Acta Biochim Pol. https://doi.org/10.1007/s00424-014-1510-6 CrossRefPubMed

Rai AK et al (2011) High concentration of adenosine in human visceral leishmaniasis despite increased ADA and decreased CD73′. Parasite Immunol 33:632–636. https://doi.org/10.1111/j.1365-3024.2011.01315.x CrossRefPubMed

Rajasekaran R, Chen YPP (2015) Potential therapeutic targets and the role of technology in developing novel antileishmanial drugs. Drug Discov Today. https://doi.org/10.1016/j.drudis.2015.04.006 CrossRefPubMed

Ready PD (2014) Epidemiology of visceral leishmaniasis. Clin Epidemiol. https://doi.org/10.2147/clep.s44267 CrossRefPubMedPubMedCentral

Robson SC, Se J, Zimmermann H (2006) The E-NTPDase family of ectonucleotidases: structure function relationships and pathophysiological significance. Purinergic Signal 2:409–430. https://doi.org/10.1007/s11302-006-9003-5 CrossRefPubMedPubMedCentral

Rodrigues V et al (2016) Regulation of immunity during visceral Leishmania infection. Parasit Vectors. https://doi.org/10.1186/s13071-016-1412-x CrossRefPubMedPubMedCentral

Saad-Nehme J et al (2004) A Mg-dependent ecto-ATPase is increased in the infective stages of Trypanosoma cruzi. Parasitol Res 93:41–50. https://doi.org/10.1007/s00436-003-1066-4 CrossRefPubMed

Sanchez MA et al (2004) ‘Functional expression and characterization of a purine nucleobase transporter gene from Leishmania major. Mol Membr Biol 21(1):11–18. https://doi.org/10.1080/0968768031000140845 CrossRefPubMed

Sansom FM et al (2014) Golgi-located NTPDase1 of Leishmania major is required for lipophosphoglycan elongation and normal lesion development whereas secreted NTPDase2 is dispensable for virulence. PLoS Negl Trop Dis 8(12):e3402. https://doi.org/10.1371/journal.pntd.0003402 CrossRefPubMedPubMedCentral

Sauvage V et al (2009) The role of ATP-binding cassette (ABC) proteins in protozoan parasites. Mol Biochem Parasitol. https://doi.org/10.1016/j.molbiopara.2009.05.005 CrossRefPubMed

Sindhu KJ, Kureel AK, Saini S, Kumari S, Verma P, Rai AK (2018) Characterization of phosphate transporter(s) and understanding their role in Leishmania donovani parasite. Acta Parasitol 63(1):75–88CrossRefPubMed

Singh N, Kumar M, Singh RK (2012) Leishmaniasis: current status of available drugs and new potential drug targets. Asian Pac J Trop Med 5(6):485–497. https://doi.org/10.1016/S1995-7645(12)60084-4 CrossRefPubMed

Składanowski A (2013) The role of soluble 5′-nucleotidases in the conversion of nucleotide analogs: metabolic and therapeutic aspects. Curr Med Chem. https://doi.org/10.2174/0929867311320340005 CrossRefPubMed

Smith DF, Peacock CS, Cruz AK (2007) Comparative genomics: from genotype to disease phenotype in the leishmaniases. Int J Parasitol. https://doi.org/10.1016/j.ijpara.2007.05.015 CrossRefPubMedPubMedCentral

Stauch A et al (2011) Visceral leishmaniasis in the indian subcontinent: modelling epidemiology and control. PLoS Negl Trop Dis. https://doi.org/10.1371/journal.pntd.0001405 CrossRefPubMedPubMedCentral

Stein A et al (2003) Equilibrative nucleoside transporter family members from Leishmania donovani are electrogenic proton symporters. J Biol Chem 278(37):35127–35134. https://doi.org/10.1074/jbc.M306188200 CrossRefPubMed

Ullman B et al (2008) Purine and pyrimidine metabolism in Leishmania. Adv Exp Med Biol. https://doi.org/10.1007/978-0-387-77570-8_12 CrossRefPubMed

Valde R et al (2004) Transmembrane domain 5 of the LdNT1. 1 nucleoside transporter is an amphipathic helix that forms part of the nucleoside. Translocat Pathw 43:6793–6802

Van Den Berghe G, Vincent MF, Marie S (2012) Disorders of purine and pyrimidine metabolism. In: Inborn metabolic diseases: diagnosis and treatment. https://doi.org/10.1007/978-3-642-15720-2_37

Vasudevan G, Ullman B, Landfear SM (2001) Point mutations in a nucleoside transporter gene from Leishmania donovani confer drug resistance and alter substrate selectivity. Proc Natl Acad Sci. https://doi.org/10.1073/pnas.101537298 CrossRefPubMed

Vieira DP et al (2011) Leishmania chagasi: an ecto-3′-nucleotidase activity modulated by inorganic phosphate and its possible involvement in parasite-macrophage interaction. Exp Parasitol 127(3):702–707. https://doi.org/10.1016/j.exppara.2010.11.003 CrossRefPubMed

Weiss PHE et al (2015) Kinetic and biochemical characterization of Trypanosoma evansi nucleoside triphosphate diphosphohydrolase. Exp Parasitol. https://doi.org/10.1016/j.exppara.2015.03.009 CrossRefPubMed

World Health Organization (2010) Control of the leishmaniases. World Health Organization technical report series. https://doi.org/10.1038/nrmicro1766

Yegutkin GG (2008) Nucleotide- and nucleoside-converting ectoenzymes: important modulators of purinergic signalling cascade. Biochim Biophys Acta Mol Cell Res. https://doi.org/10.1016/j.bbamcr.2008.01.024 CrossRef

Young JD et al (2008) Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica. https://doi.org/10.1080/00498250801927427 CrossRefPubMed

Zimmermann H (2001) Ectonucleotidases: some recent developments and a note on nomenclature. Drug Dev Res. https://doi.org/10.1002/ddr.1097 CrossRefPubMedCentral

Title: Dependence of Leishmania parasite on host derived ATP: an overview of extracellular nucleotide metabolism in parasite
Authors: Kashika Arora
Ambak Kumar Rai
Publication date: 01-03-2019
Publisher: Springer India
Published in: Journal of Parasitic Diseases / Issue 1/2019
Print ISSN: 0971-7196
Electronic ISSN: 0975-0703
DOI: https://doi.org/10.1007/s12639-018-1061-4

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Dependence of Leishmania parasite on host derived ATP: an overview of extracellular nucleotide metabolism in parasite

Abstract

Graphical abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Graphical abstract

Please log in to get access to this content

Other articles of this Issue 1/2019

First report of Posthodiplostomum minimum metacercariae and resulting histopathological changes in Bagrus bajad from Lake Nasser, Egypt

An optimized assay for detecting Encephalitozoon intestinalis and Enterocytozoon bieneusi in dairy calf feces using polymerase chain reaction technology

Validity of a new immunochromatographic test in detection of Toxoplasma gondii in cancer patients

TREM-1 modulation produces positive outcome on the histopathology and cytokines release profile of Plasmodium berghei-infected mice

Cross-sectional study of Eimeria species of poultry in Kwara State, North-Central Nigeria

Molecular identification of two cestodes species parasitizing freshwater fishes in India

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page