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Volume 149, Issue 12

High-affinity -inositol transport in : substrate specificity and pharmacology Free

Abstract

Inositol is considered a growth factor in yeast cells and it plays an important role in as an essential precursor for phospholipomannan, a glycophosphatidylinositol (GPI)-anchored glycolipid on the cell surface of which is involved in the pathogenicity of this opportunistic fungus and which binds to and stimulates human macrophages. In addition, inositol plays an essential role in the phosphatidylinositol signal transduction pathway, which controls many cell cycle events. Here, high-affinity -inositol uptake in has been characterized, with an apparent value of 240±15 μM, which appears to be active and energy-dependent as revealed by inhibition with azide and protonophores (FCCP, dinitrophenol). -inositol transport was sodium-independent but proton-coupled with an apparent value of 11·0±1·1 nM for H, equal pH 7·96±0·05, suggesting that the -inositol–H transporter is fully activated at physiological pH. inositol transport was not affected by cytochalasin B, phloretin or phlorizin, an inhibitor of mammalian sodium-dependent inositol transport. Furthermore, -inositol transport showed high substrate specificity for inositol and was not significantly affected by hexose or pentose sugars as competitors, despite their structural similarity. Transport kinetics in the presence of eight different inositol isomers as competitors revealed that proton bonds between the C-2, C-3 and C-4 hydroxyl groups of -inositol and the transporter protein play a critical role for substrate recognition and binding. It is concluded that -inositol–H transport differs kinetically and pharmacologically from the human sodium-dependent -inositol transport system and constitutes an attractive target for delivery of cytotoxic inositol analogues in this pathogenic fungus.

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Keyword(s): FCCP, carbonylcyanide-4-(trifluoromethoxy) phenylhydrazone and GPI, glycophosphatidylinositol
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2003-12-01
2024-04-25
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References

  1. Atkinson K. D., Kolat A. I., Henry S. A. 1977; Osmotic imbalance in inositol-starved spheroplasts of Saccharomyces cerevisiae . J Bacteriol 132:806–817
     [Google Scholar]
  2. Baldwin S. A. 1993; Mammalian passive glucose transporters: members of an ubiquitous family of active and passive transport proteins. Biochim Biophys Acta 115417–49
     [Google Scholar]
  3. Berridge M. J. 1993; Inositol trisphosphate and calcium signalling. Nature 361:315–325
     [Google Scholar]
  4. Bisswanger H. 2002; Analysis of enzyme kinetic data. In Enzyme Kinetics: Principles and Methods pp 58–75 Weinheim, Germany: Wiley-VCH;
     [Google Scholar]
  5. Brown A. J. P. 2002; Morphogenetic signaling pathways in Candida albicans . In Candida and Candidiasis pp 95–106 Edited by Calderone R. A. Washington, DC: American Society for Microbiology;
     [Google Scholar]
  6. Bruckmann A., Kunkel W., Hartl A., Wetzker R., Eck R. 2000; A phosphatidylinositol 3-kinase of Candida albicans influences adhesion, filamentous growth and virulence. Microbiology 146:2755–2764
     [Google Scholar]
  7. Carman G. M., Henry S. A. 1989; Phospholipid biosynthesis in yeast. Annu Rev Biochem 58:635–669
     [Google Scholar]
  8. Cheneval J. P., Deshusses J., Posternak T. 1970; Sur le transport de l'inositol chez Schizosaccharomyces pombe . Biochim Biophys Acta 203:348–350
     [Google Scholar]
  9. Coady M. J., Wallendorff B., Gagnon D. G., Lapointe J.-Y. 2002; Identification of a novel Na+/ myo -inositol cotransporter. J Biol Chem 277:35219–35224
     [Google Scholar]
  10. Cowen L. E., Nantel A., Whiteway M. S., Thomas D. Y., Tessier D. C., Kohn L. M., Anderson J. B. 2002; Population genomics of drug resistance in Candida albicans . Proc Natl Acad Sci U S A 99:9284–9289
     [Google Scholar]
  11. Cutler J. E. 1991; Putative virulence factors of Candida albicans . Annu Rev Microbiol 45:187–218
     [Google Scholar]
  12. Dean-Johnson M., Henry S. A. 1989; Biosynthesis of inositol in yeast: primary structure of myo -inositol-1-phosphate synthase (EC 5.5.1.4) and functional analysis of its structural gene, the INO1 locus. J Biol Chem 264:1274–1283
     [Google Scholar]
  13. de Leon E. M., Jacober S. J., Sobel J. D., Foxman B. 2002; Prevalence and risk factors for vaginal Candida colonization in women with type 1 and type 2 diabetes. BMC Infect Dis 2:1–6
     [Google Scholar]
  14. Deshusses J., Reber G. 1977; myo -Inositol transport in Klebsiella aerogenes : scyllo -Inositol, a non-metabolizable substrate for the study of the myo -inositol transport system. Eur J Biochem 72:87–91
     [Google Scholar]
  15. Deshusses J., Cheneval J. P., Posternak T. 1969; Recherches biochimiques sur Schizosaccharomyces pombe en fonction des conditions de culture et de l'action d'inhibiteurs: I. Étude des phospholipides. Biochim Biophys Acta 176:789–802
     [Google Scholar]
  16. Drew M. E., Langford C. K., Klamo E. M., Russell D. G., Kavanaugh M. P., Landfear S. M. 1995; Functional expression of a myo -inositol/H+ symporter from Leishmania donovani . Mol Cell Biol 15:5508–5515
     [Google Scholar]
  17. Fernandez S., Homann M. J., Henry S. A., Carman G. M. 1986; Metabolism of the phospholipid precursor inositol and its relationship to growth and viability in the natural auxotroph Schizosaccharomyces pombe . J Bacteriol 166:779–786
     [Google Scholar]
  18. Garcia J. C., Strube M., Leingang K., Keller K., Mueckler M. M. 1992; Amino acid substitutions at tryptophan 388 and tryptophan 412 of HepG2 (Glut1) glucose transporter inhibit transport activity and targeting to the plasma membrane in Xenopus oocytes. J Biol Chem 267:7770–7776
     [Google Scholar]
  19. Georgopapadakou N. H., Walsh T. J. 1996; Antifungal agents: chemotherapeutic targets and immunologic strategies. Antimicrob Agents Chemother 40:279–291
     [Google Scholar]
  20. Goswami R., Dadhwal V., Tejaswi S., Datta K., Paul A., Haricharan R. N., Banerjee U., Kochupillai N. P. 2000; Species-specific prevalence of vaginal candidiasis among patients with diabetes mellitus and its relation to their glycaemic status. J Infect 41:162–166
     [Google Scholar]
  21. Greenberg M. L., Lopes J. M. 1996; Genetic regulation of phospholipid biosynthesis in Saccharomyces cerevisiae . Microbiol Rev 60:1–20
     [Google Scholar]
  22. Hager K., Hazama A., Kwon H. M., Loo D. D. F., Handler J. S., Wright E. M. 1995; Kinetics and specificity of the renal Na+/ myo -inositol cotransporter expressed in Xenopus oocytes. J Membr Biol 143:103–113
     [Google Scholar]
  23. Henderson P. J. F. 1991; Sugar transport proteins. Curr Opin Struct Biol 1:590–601
     [Google Scholar]
  24. Ingavale S. S., Bachhawat A. K. 1999; Restoration of inositol prototrophy in the fission yeast Schizosaccharomyces pombe . Microbiology 145:1903–1910
     [Google Scholar]
  25. Johnson S. C., Dahl J., Shih T.-L., Schedler D. J. A., Anderson L., Benjamin T. L., Baker D. C. 1993; Synthesis and evaluation of 3-modified 1 d- myo -inositols as inhibitors and substrates of phosphatidylinositol synthase and inhibitors of myo -inositol uptake by cells. J Med Chem 36:3628–3635
     [Google Scholar]
  26. Jouault T., Bernigaud A., Lepage G., Trinel P., Poulain D. 1994; The Candida albicans phospholipomannan induces in vitro production of tumour necrosis factor-alpha from human and murine macrophages. Immunology 83:268–273
     [Google Scholar]
  27. Klig L. S., Antonsson B., Schmid E., Friedli L. 1991; Inositol biosynthesis: Candida albicans and Saccharomyces cerevisiae genes share common regulation. Yeast 7:325–336
     [Google Scholar]
  28. Kouzuma T., Takahashi M., Endoh T., Kaneko R., Ura N., Shimamoto K., Watanabe N. 2001; An enzymatic cycling method for the measurement of myo -inositol in biological samples. Clin Chim Acta 312:143–151
     [Google Scholar]
  29. Kwon H. M., Yamauchi A., Uchida S., Preston A. S., Garcia-Perez A., Burg M. B., Handler J. S. 1992; Cloning of the cDNA for a Na+/ myo -inositol cotransporter, a hypertonicity stress protein. J Biol Chem 267:6297–6301
     [Google Scholar]
  30. Lai K., McGraw P. 1994; Dual control of inositol transport in Saccharomyces cerevisiae by irreversible inactivation of permease and regulation of permease synthesis by INO2 , INO4 , and OPI1 . J Biol Chem 269:2245–2251
     [Google Scholar]
  31. Lai K., Bolognese C. P., Swift S., McGraw P. 1995; Regulation of inositol transport in Saccharomyces cerevisiae involves inositol-induced changes in permease stability and endocytic degradation in the vacuole. J Biol Chem 270:2525–2534
     [Google Scholar]
  32. Leidich S. D., Drapp D. A., Orlean P. 1994; A conditionally lethal yeast mutant blocked at the first step in glycosyl phosphatidylinositol anchor synthesis. J Biol Chem 269:10193–10196
     [Google Scholar]
  33. Lentner C. 1981; Cerebrospinal fluid. In Geigy Scientific Tables , Body Fluids vol. 1 pp 165–177 Basle, Switzerland: Ciba-Geigy;
     [Google Scholar]
  34. Matskevitch J., Wagner C. A., Risler T., Kwon H. M., Handler J. S., Waldegger S., Busch A. E., Lang F. 1994; Effect of extracellular pH on the myo -inositol transporter SMIT expressed in Xenopus oocytes. Eur J Physiol 436:854–857
     [Google Scholar]
  35. McConville M. J., Ferguson M. A. J. 1993; The structure, biosynthesis and function of glycosylated phosphatidylinositols in the parasitic protozoa and higher eukaryotes. Biochem J 294:305–324
     [Google Scholar]
  36. Molina Y., Ramos S. E., Douglass T., Klig L. S. 1999; Inositol synthesis and catabolism in Cryptococcus neoformans . Yeast 15:1657–1667
     [Google Scholar]
  37. Murray M., Greenberg M. L. 2000; Expression of yeast INM1 encoding inositol monophosphatase is regulated by inositol, carbon source and growth stage and is decreased by lithium and valproate. Mol Microbiol 36:651–661
     [Google Scholar]
  38. Nikawa J., Nagumo T., Yamashita S. 1982; myo -Inositol transport in Saccharomyces cerevisiae . J Bacteriol 150:441–446
     [Google Scholar]
  39. Nikawa J., Tsukagoshi Y., Yamashita S. 1991; Isolation and characterization of two distinct myo -inositol transporter genes of Saccharomyces cerevisiae . J Biol Chem 266:11184–11191
     [Google Scholar]
  40. Nikawa J., Hosaka K., Yamashita S. 1993; Differential regulation of two myo -inositol transporter genes of Saccharomyces cerevisiae . Mol Microbiol 10:955–961
     [Google Scholar]
  41. Offer J., Metcalfe J. C., Smith G. A. 1993; The uptake of 3H-labelled monodeoxyfluoro- myo -inositols into thymocytes and their incorporation into phospholipid in permeabilized cells. Biochem J 291:553–560
     [Google Scholar]
  42. Ostlund R. E. Jr, McGill J. B., Herskowitz I., Kipnis D. M., Santiago J. V., Sherman W. R. 1993; d- chiro -Inositol metabolism in diabetes mellitus. Proc Natl Acad Sci U S A 90:9988–9992
     [Google Scholar]
  43. Pfaller M. A., Jones R. N., Messer S. A., Edmond M. B., Wenzel R. P. 1998; National surveillance of nosocomial blood stream infections due to Candida albicans : frequency of occurrence and antifungal susceptibility in the SCOPE program. Diagn Microbiol Infect Dis 31:327–332
     [Google Scholar]
  44. Powis G., Aksoy I. A., Melder D. C., Aksoy S., Eichinger H., Fauq A. H., Kozikowski A. P. 1991; d-3-Deoxy-3-substituted myo -inositol analogues as inhibitors of cell growth. Cancer Chemother Pharmacol 29:95–104
     [Google Scholar]
  45. Reber G., Belet M., Deshusses J. 1977; myo -Inositol transport system in Pseudomonas putida . J Bacteriol 131:872–875
     [Google Scholar]
  46. Reizer J., Reizer A., Saier M. H. Jr 1994; A functional superfamily of sodium/solute symporters. Biochim Biophys Acta 1197133–166
     [Google Scholar]
  47. Schopfer W. H., Posternak T., Wustenfeld D. 1962; Recherches sur le rôle du méso-inositol dans la biologie cellulaire de Schizosaccharomyces pombe Lindner. Arch Mikrobiol 44:113–151
     [Google Scholar]
  48. Seyfang A., Duszenko M. 1991; Specificity of glucose transport in Trypanosoma brucei : effective inhibition by phloretin and cytochalasin B. Eur J Biochem 202:191–196
     [Google Scholar]
  49. Seyfang A., Landfear S. M. 2000; Four conserved cytoplasmic sequence motifs are important for transport function of the Leishmania inositol/H+ symporter. J Biol Chem 275:5687–5693
     [Google Scholar]
  50. Seyfang A., Kavanaugh M. P., Landfear S. M. 1997; Aspartate 19 and glutamate 121 are critical for transport function of the myo -inositol/H+ symporter from Leishmania donovani . J Biol Chem 272:24210–24215
     [Google Scholar]
  51. Sima A. A., Dunlap J. A., Davidson E. P., Wiese T. J., Lightle R. L., Greene D. A., Yorek M. A. 1997; Supplemental myo -inositol prevents l-fucose-induced diabetic neuropathy. Diabetes 46:301–306
     [Google Scholar]
  52. Simonsen A., Wurmser A. E., Emr S. E., Stenmark H. 2001; The role of phosphoinositides in membrane transport. Curr Opin Cell Biol 13:485–492
     [Google Scholar]
  53. Soll D. R. 2002; Phenotypic switching. In Candida and Candidiasis pp 123–142 Edited by Calderone R. A. Washington, DC: American Society for Microbiology Press;
     [Google Scholar]
  54. Sütterlin C., Horvarth A., Gerold P., Scharz R. T., Wang Y., Dreyfuss M., Riezman H. 1997; Identification of a species-specific inhibitor of glycosylphosphatidylinositol synthesis. EMBO J 16:6374–6383
     [Google Scholar]
  55. Trinel P.-A., Plancke Y., Gerold P., Jouault T., Delplace F., Schwarz R. T., Strecker G., Poulain D. 1999; The Candida albicans phospholipomannan is a family of glycolipids presenting phosphoinositolmannosides with long linear chains of β -1,2-linked mannose residues. J Biol Chem 274:30520–30526
     [Google Scholar]
  56. Turk E., Wright E. M. 1997; Membrane topology motifs in SGLT cotransporter family. J Membr Biol 159:1–20
     [Google Scholar]
  57. Ulaszewski S., Woodward J. R., Cirillo V. P. 1978; Membrane damage associated with inositol-less death in Saccharomyces cerevisiae . J Bacteriol 136:49–54
     [Google Scholar]
  58. Uldry M., Ibberson M., Horisberger J.-D., Chatton J.-Y., Riederer B. M., Thorens B. 2001; Identification of a mammalian H+- myo -inositol symporter expressed predominantly in the brain. EMBO J 20:4467–4477
     [Google Scholar]
  59. Vanden Bossche H., Dromer F., Improvisi I., Lozano-Chiu M., Rex J. H., Sanglard D. 1998; Antifungal drug resistance in pathogenic fungi. Med Mycol 36:Suppl 1119–128
     [Google Scholar]
  60. Walmsley A. R., Barrett M. P., Bringaud F., Gould G. W. 1998; Sugar transporters from bacteria, parasites and mammals: structure-activity relationships. Trends Biochem Sci 23:476–481
     [Google Scholar]
  61. Wiedemann C., Cockcroft S. 1998; Vesicular transport: sticky fingers grab a lipid. Nature 394:426–427
     [Google Scholar]
  62. Zar J. H. 1984; Paired-sample hypotheses. In Biostatistical Analysis , 2nd edn. pp 150–153 Eaglewood Cliffs, NJ: Prentice Hall;
     [Google Scholar]
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High-affinity myo-inositol transport in Candida albicans: substrate specificity and pharmacology
Microbiology 149, 3371 (2003); https://doi.org/10.1099/mic.0.26644-0
/content/journal/micro/10.1099/mic.0.26644-0
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