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. 2002 Dec 15;368(Pt 3):923–929. doi: 10.1042/BJ20021189

Comparative characterization of hexose transporters of Plasmodium knowlesi, Plasmodium yoelii and Toxoplasma gondii highlights functional differences within the apicomplexan family.

Thierry Joët 1, Lennart Holterman 1, Timothy T Stedman 1, Clemens H M Kocken 1, Annemarie Van Der Wel 1, Alan W Thomas 1, Sanjeev Krishna 1
PMCID: PMC1223042  PMID: 12238947

Abstract

Chemotherapy of apicomplexan parasites is limited by emerging drug resistance or lack of novel targets. PfHT1, the Plasmodium falciparum hexose transporter 1, is a promising new drug target because asexual-stage malarial parasites depend wholly on glucose for energy. We have performed a comparative functional characterization of PfHT1 and hexose transporters of the simian malarial parasite P. knowlesi (PkHT1), the rodent parasite P. yoelii (PyHT1) and the human apicomplexan parasite Toxoplasma gondii ( T. gondii glucose transporter 1, TgGT1). PkHT1 and PyHT1 share >70% amino acid identity with PfHT1, while TgGT1 is more divergent (37.2% identity). All transporters mediate uptake of D-glucose and D-fructose. PyHT1 has an affinity for glucose ( K (m) approximately 0.12 mM) that is higher than that for PkHT1 ( K (m) approximately 0.67 mM) or PfHT1 ( K (m) approximately 1 mM). TgGT1 is highly temperature dependent (the Q (10) value, the fold change in activity for a 10 degrees C change in temperature, was >7) compared with Plasmodium transporters ( Q (10), 1.5-2.5), and overall has the highest affinity for glucose ( K (m) approximately 30 microM). Using active analogues in competition for glucose uptake, experiments show that hydroxyl groups at the C-3, C-4 and C-6 positions are important in interacting with PkHT1, PyHT1 and TgGT1. This study defines models useful to study the biology of apicomplexan hexose permeation pathways, as well as contributing to drug development.

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Selected References

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  1. Arbuckle M. I., Kane S., Porter L. M., Seatter M. J., Gould G. W. Structure-function analysis of liver-type (GLUT2) and brain-type (GLUT3) glucose transporters: expression of chimeric transporters in Xenopus oocytes suggests an important role for putative transmembrane helix 7 in determining substrate selectivity. Biochemistry. 1996 Dec 24;35(51):16519–16527. doi: 10.1021/bi962210n. [DOI] [PubMed] [Google Scholar]
  2. CHIN W., CONTACOS P. G., COATNEY G. R., KIMBALL H. R. A NATURALLY ACQUITED QUOTIDIAN-TYPE MALARIA IN MAN TRANSFERABLE TO MONKEYS. Science. 1965 Aug 20;149(3686):865–865. doi: 10.1126/science.149.3686.865. [DOI] [PubMed] [Google Scholar]
  3. Escalante A. A., Ayala F. J. Evolutionary origin of Plasmodium and other Apicomplexa based on rRNA genes. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):5793–5797. doi: 10.1073/pnas.92.13.5793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Escalante A. A., Freeland D. E., Collins W. E., Lal A. A. The evolution of primate malaria parasites based on the gene encoding cytochrome b from the linear mitochondrial genome. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8124–8129. doi: 10.1073/pnas.95.14.8124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Greenwood Brian, Mutabingwa Theonest. Malaria in 2002. Nature. 2002 Feb 7;415(6872):670–672. doi: 10.1038/415670a. [DOI] [PubMed] [Google Scholar]
  6. Helgerson A. L., Carruthers A. Analysis of protein-mediated 3-O-methylglucose transport in rat erythrocytes: rejection of the alternating conformation carrier model for sugar transport. Biochemistry. 1989 May 30;28(11):4580–4594. doi: 10.1021/bi00437a012. [DOI] [PubMed] [Google Scholar]
  7. Hruz P. W., Mueckler M. M. Structural analysis of the GLUT1 facilitative glucose transporter (review). Mol Membr Biol. 2001 Jul-Sep;18(3):183–193. doi: 10.1080/09687680110072140. [DOI] [PubMed] [Google Scholar]
  8. Izumo A., Tanabe K., Kato M., Doi S., Maekawa K., Takada S. Transport processes of 2-deoxy-D-glucose in erythrocytes infected with Plasmodium yoelii, a rodent malaria parasite. Parasitology. 1989 Jun;98(Pt 3):371–379. doi: 10.1017/s0031182000061448. [DOI] [PubMed] [Google Scholar]
  9. Kirk K., Horner H. A., Kirk J. Glucose uptake in Plasmodium falciparum-infected erythrocytes is an equilibrative not an active process. Mol Biochem Parasitol. 1996 Nov 25;82(2):195–205. doi: 10.1016/0166-6851(96)02734-x. [DOI] [PubMed] [Google Scholar]
  10. Kocken Clemens H. M., Ozwara Hastings, van der Wel Annemarie, Beetsma Annette L., Mwenda Jason M., Thomas Alan W. Plasmodium knowlesi provides a rapid in vitro and in vivo transfection system that enables double-crossover gene knockout studies. Infect Immun. 2002 Feb;70(2):655–660. doi: 10.1128/IAI.70.2.655-660.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Krishna S., Woodrow C. J., Burchmore R. J., Saliba K. J., Kirk K. Hexose transport in asexual stages of Plasmodium falciparum and kinetoplastidae. Parasitol Today. 2000 Dec;16(12):516–521. doi: 10.1016/s0169-4758(00)01762-2. [DOI] [PubMed] [Google Scholar]
  12. Manning Suzanne K., Woodrow Charles, Zuniga Felipe A., Iserovich Pavel, Fischbarg Jorge, Louw Abraham I., Krishna Sanjeev. Mutational analysis of the hexose transporter of Plasmodium falciparum and development of a three-dimensional model. J Biol Chem. 2002 May 31;277(34):30942–30949. doi: 10.1074/jbc.M204337200. [DOI] [PubMed] [Google Scholar]
  13. Naftalin R. J., Rist R. J. 3-O-methyl-D-glucose transport in rat red cells: effects of heavy water. Biochim Biophys Acta. 1991 Apr 26;1064(1):37–48. doi: 10.1016/0005-2736(91)90409-2. [DOI] [PubMed] [Google Scholar]
  14. Ohsaka A., Yoshikawa K., Hagiwara T. 1H-NMR spectroscopic study of aerobic glucose metabolism in Toxoplasma gondii harvested from the peritoneal exudate of experimentally infected mice. Physiol Chem Phys. 1982;14(4):381–384. [PubMed] [Google Scholar]
  15. Pasquier C., Promponas V. J., Palaios G. A., Hamodrakas J. S., Hamodrakas S. J. A novel method for predicting transmembrane segments in proteins based on a statistical analysis of the SwissProt database: the PRED-TMR algorithm. Protein Eng. 1999 May;12(5):381–385. doi: 10.1093/protein/12.5.381. [DOI] [PubMed] [Google Scholar]
  16. Peier Andrea M., Reeve Alison J., Andersson David A., Moqrich Aziz, Earley Taryn J., Hergarden Anne C., Story Gina M., Colley Sian, Hogenesch John B., McIntyre Peter. A heat-sensitive TRP channel expressed in keratinocytes. Science. 2002 May 16;296(5575):2046–2049. doi: 10.1126/science.1073140. [DOI] [PubMed] [Google Scholar]
  17. Ridley Robert G. Medical need, scientific opportunity and the drive for antimalarial drugs. Nature. 2002 Feb 7;415(6872):686–693. doi: 10.1038/415686a. [DOI] [PubMed] [Google Scholar]
  18. Seatter M. J., De la Rue S. A., Porter L. M., Gould G. W. QLS motif in transmembrane helix VII of the glucose transporter family interacts with the C-1 position of D-glucose and is involved in substrate selection at the exofacial binding site. Biochemistry. 1998 Feb 3;37(5):1322–1326. doi: 10.1021/bi972322u. [DOI] [PubMed] [Google Scholar]
  19. Tetaud E., Chabas S., Giroud C., Barrett M. P., Baltz T. Hexose uptake in Trypanosoma cruzi: structure-activity relationship between substrate and transporter. Biochem J. 1996 Jul 15;317(Pt 2):353–359. doi: 10.1042/bj3170353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Woodrow C. J., Burchmore R. J., Krishna S. Hexose permeation pathways in Plasmodium falciparum-infected erythrocytes. Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):9931–9936. doi: 10.1073/pnas.170153097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Woodrow C. J., Penny J. I., Krishna S. Intraerythrocytic Plasmodium falciparum expresses a high affinity facilitative hexose transporter. J Biol Chem. 1999 Mar 12;274(11):7272–7277. doi: 10.1074/jbc.274.11.7272. [DOI] [PubMed] [Google Scholar]

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