The Structure and Mechanism of myo-Inositol-1-Phosphate Synthase

  • James H. Geiger
  • Xiangshu Jin
Part of the Subcellular Biochemistry book series (SCBI, volume 39)


The first and rate-limiting step in the biosynthesis of myo-inositol is the conversion of D-glucose 6-phosphate to 1L-myo-inositol 1-phosphate catalyzed by 1L-myo-inositol 1-phosphate synthase (MIP synthase). MIP synthase has been identified in a wide variety of organisms from bacteria to humans and is relatively well-conserved throughout evolution. It is probably homotetrameric in most if not all cases and always requires NAD+ as a cofactor, with NADH being reconverted to NAD+ in the catalytic cycle. This review focuses on the structure and mechanism of MIP synthase, with a particular emphasis on the mechanistic insights that have come from several recent structures of the enzyme. These include the structure of the enzyme from Saccharomyces cerevisiae, Archeoglobus fulgidus and Mycobacterium tuberculosis.


Inositol biosynthesis 1L-myo-inositol 1-phosphate synthase D-glucose 6-phosphate enzyme structure enzyme mechanism 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barnett, J.E., and Corina, D.L., 1968, The mechanism of glucose 6-phosphate-D-myo-inositol 1-phosphate cyclase of rat testis. The involvement of hydrogen atoms. Biochem. J. 108: 125–129.PubMedGoogle Scholar
  2. Barnett, J.E.G., Rasheed, A., and Corina, D.L., 1973a, Inhibitors of MIP synthase. Biochem. Soc. Trans. 1: 1267.PubMedGoogle Scholar
  3. Barnett, J.E.G., Rasheed, A., and Corina, D.L., 1973b, Partial reactions of D-glucose 6-phosphate-1l-myoinositol 1-phosphate cyclase. Biochem. J. 131: 21–30.PubMedGoogle Scholar
  4. Bender, S.L., Widlanski, T., and Knowles, J.R., 1989, Dehydroquinate synthase — the use of substrate-analogs to probe the early steps of the catalyzed reaction. Biochemistry 28: 7560–7572.PubMedCrossRefGoogle Scholar
  5. Bohnert, H.J., and Jensen, R.G., 1996, Strategies for engineering water-stress tolerance in plants. Trends Biotechnol. 14: 89–97.CrossRefGoogle Scholar
  6. Byun, S.M., and Jenness, R., 1981, Stereospecificity of L-myo-inositol-1-phosphate synthase for nicotinamide adenine dinucleotide. Biochemistry 20: 5174–5177.PubMedCrossRefGoogle Scholar
  7. Byun, S.M., Jenness, R., Ridley, W.P., and Kirkwood, S., 1973, Stereospecificity of D-glucose-6-phosphate — 1l-myo-inositol-1-phosphate cycloaldolase on hydrogen-atoms at C-6. Biochem. Biophys. Res. Commun. 54: 961–967.PubMedCrossRefGoogle Scholar
  8. Chen, C.H.J., and Eisenberg, F., 1975, Myoinosose-2 1-phosphate-intermediate in myoinositol 1-phosphate synthase reaction. J. Biol. Chem. 250: 2963–2967.PubMedGoogle Scholar
  9. Chen, I.W., and Charalampous, F.C., 1965, Biochemical studies on inositol. 8. Purification and properties of the enzyme system which converts glucose 6-phosphate to inositol. J. Biol. Chem. 240: 3507–3512.PubMedGoogle Scholar
  10. Chen, I.W., and Charalampous, F.C., 1967, Studies on the mechanism of cyclization of glucose 6-phosphate to D-inositol 1-phosphate. Biochim. Biophys. Acta. 136: 568–570.PubMedGoogle Scholar
  11. Chen, L., Zhou, C., Yang, H., and Roberts, M.F., 2000a, Inositol-1-phosphate synthase from Archaeoglobus fulgidus is a class II adolase. FASEB J. 14: 77.Google Scholar
  12. Chen, L.J., Zhou, C., Yang, H.Y., and Roberts, M.F., 2000b, Inositol-1-phosphate synthase from Archaeoglobus fulgidus is a class II aldolase. Biochemistry 39: 12415–12423.PubMedCrossRefGoogle Scholar
  13. Conrad, R.M., Grogan, M.J., and Bertozzi, C.R., 2002, Stereloselective synthesis of myo-inositol via ring-closing metathesis: A building block for glycosylphosphatidylinositol (GPI) anchor synthesis. Org. Lett. 4: 1359–1361.PubMedCrossRefGoogle Scholar
  14. Dreyer, M.K., and Schulz, G.E., 1996, Catalytic mechanism of the metal-dependent fuculose aldolase from Escherichia coli as derived from the structure. J. Mol. Biol. 259: 458–466.PubMedCrossRefGoogle Scholar
  15. Eisenberg, F., Jr., 1967, D-myoinositol 1-phosphate as product of cyclization of glucose 6-phosphate and substrate for a specific phosphatase in rat testis. J. Biol. Chem. 242: 1375–1382.PubMedGoogle Scholar
  16. Fischer, H.O.L., 1945, Chemical and biochemical relationships between hexoses and inositols. Harvey Lect. 40: 156–178.Google Scholar
  17. Gumber, S.C., Loewus, M.W., and Loewus, F.A., 1984, Further-studies on myo-inositol-1-phosphatase from the pollen of lilium-longiflorum thunb. Plant Physiol. 76: 40–44.PubMedGoogle Scholar
  18. Hoffmann-Ostenhof, O., and Pittner, F., 1982, The biosynthesis of myo-inositol and its isomers. Can. J. Chem. 60: 1863–1871.CrossRefGoogle Scholar
  19. Horecker, B.L., Tsolas, O., and Lai, C.Y., 1972, Aldolases. In: Boyer, P.D. (ed.), The Enzymes, Vol. 7. Academic Press, New York, pp. 213–258.Google Scholar
  20. Jin, X.S., Foley, K.M., and Geiger, J.H., 2004, The structure of the 1L-myo-inositol-1-phosphate synthase-NAD(+)-2deoxy-D-glucitol 6-(E)-vinylhomophosphonate complex demands a revision of the enzyme mechanism. J. Biol. Chem. 279: 13889–13895.PubMedCrossRefGoogle Scholar
  21. Jin, X.S., and Geiger, J.H., 2003, Structures of NAD(+)-and NADH-bound 1-L-myo-inositol 1-phosphate synthase. Acta Crystallogr Section D-Biol. Crystallogr. 59: 1154–1164.CrossRefGoogle Scholar
  22. Kiely, D.E., and Sherman, W.R., 1975, Chemical model for cyclization step in biosynthesis of L-myo-inositol 1-phosphate. J. Am. Chem. Soc. 97: 6810–6814.PubMedCrossRefGoogle Scholar
  23. Kniewel, R., Buglino, J.A., Shen, V., Chadya, T., Beckwith, A., and Lima, C.D., 2002, Structural analysis of Saccharomyces cerevisiae myo-inositol phosphate synthase. J. Struct. Funct. Genomics 2: 129–134.PubMedCrossRefGoogle Scholar
  24. Lee, J.K., and Houk, K.N., 1997, A proficient enzyme revisited: The predicted mechanism for orotidine monophosphate decarboxylase. Science 276: 942–945.PubMedCrossRefGoogle Scholar
  25. Loewus, F.A., 1990, Inositol biosynthesis. In: Morre, D.J., Boss, W.F., and Loewus, F.A. (eds.), Inositol Metabolism in Plants. Wiley-Liss Inc., New York, NY, pp. 13–19.Google Scholar
  26. Loewus, F.A., and Loewus, M.W., 1983, Myo-inositol: Its biosynthesis and metabolism. Annu. Rev. Plant Physiol. 34: 137–161.CrossRefGoogle Scholar
  27. Loewus, F.A., and Kelly, S., 1962, Conversion of glucose to inositol in parsley leaves. Biochem. Biophys. Res. Commun. 7: 204–208.PubMedCrossRefGoogle Scholar
  28. Loewus, F.A., and Murthy, P.P.N., 2000, Myo-inositol metabolism in plants. Plant Sci. 150: 1–19.CrossRefGoogle Scholar
  29. Loewus, M.W., 1977, Hydrogen isotope effects in the cyclization of D-glucose 6-phosphate by myo-inositol-1-phosphate synthase. J. Biol. Chem. 252: 7221–7223.PubMedGoogle Scholar
  30. Loewus, M.W., Loewus, F.A., Brillinger, G.U., Otsuka, H., and Floss, H.G., 1980, Stereochemistry of the myo-inositol-1-phosphate synthase reaction. J. Biol. Chem. 255: 11710–11712.PubMedGoogle Scholar
  31. Maeda, T., and Eisenberg, F., Jr., 1980, Purification, structure, and catalytic properties of L-myoinositol-1-phosphate synthase from rat testis. J. Biol. Chem. 255: 8458–8464.PubMedGoogle Scholar
  32. Majumder, A.L., Chatterjee, A., Dastidar, K.G., and Majee, M., 2003, Diversification and evolution of L-myo-inositol 1-phosphate synthase. FEBS Lett. 553: 3–10.PubMedCrossRefGoogle Scholar
  33. Majumder, A.L., Johnson, M.D., and Henry, S.A., 1997, 1L-myo-inositol-1-phosphate synthase. Biochim. Biophys. Acta. 1348: 245–256.PubMedGoogle Scholar
  34. Mauck, L.A., Wong, Y.H., and Sherman, W.R., 1980, L-myo-Inositol-1-phosphate synthase from bovine testis: Purification to homogeneity and partial characterization. Biochemistry 19: 3623–3629.PubMedCrossRefGoogle Scholar
  35. Migaud, M.E., and Frost, J.W., 1995, Inhibition of myo-Inositol-1-phophate Synthase by a Reaction Coordinate Intermediate. J. Am. Chem. Soc. 117: 5154–5155.CrossRefGoogle Scholar
  36. Migaud, M.E., and Frost, J.W., 1996, Elaboration of a general strategy for inhibition of myoinositol 1-phosphate synthase: Active site interactions of analogues possessing oxidized reaction centers. J. Am. Chem. Soc. 118: 495–501.CrossRefGoogle Scholar
  37. Norman, R.A., Mcalister, M.S.B., Murray-Rust, J, Movahedzadeh, F, Stoker, N.G., and Mcdonald, N. Q., 2002, Crystal structure of Inositol 1-Phosphate Synthase from Mycobacterium tuberculosis, a key enzyme in phophatidylinositol synthesis. Structure 10: 393–402.PubMedCrossRefGoogle Scholar
  38. Obendorf, R.L., 1997, Oligosaccharides and galactosyl cyclitols in seed desiccation tolerance. Seed Sci. Res. 7: 63–74.CrossRefGoogle Scholar
  39. Ogunyemi, E.O., Pittner, F., and Hoffmannostenhof, O., 1978, Studies on biosynthesis of cyclitols 36. Purification of myo-inositol-1-phosphate synthase of duckweed, Lemna-Gibba, to homogeneity by affinity chromatography on nad-sepharose molecular and catalytic properties of enzyme. Hoppe-Seylers Zeitschrift Fur Physiologische Chemie 359: 613–616.Google Scholar
  40. Parthasarathy, R., and Eisenberg, F., 1986, The inositol phospholipids — a stereochemical view of biological-activity. Biochem. J. 235: 313–322.PubMedGoogle Scholar
  41. Peng, J. (1996) Mechanistic Studies and Inhibition of Dehydroquinate Synthase and Myo-Inositol 1-Phosphate Synthase. Ph.D. Thesis, Michigan State University.Google Scholar
  42. Peterbauer, T., Puschenreiter, M., and Richter, A., 1998a, Metabolism of galactosylononitol in seeds of Vigna umbellata. Plant Cell Physiol. 39: 334–341.Google Scholar
  43. Peterbauer, T., and Richter, A., 1998b, Galactosylononitol and stachyose synthesis in seeds of adzuki bean — purification and characterization of stachyose synthase. Plant Physiol. 117: 165–172.PubMedCrossRefGoogle Scholar
  44. Pittner, F., and Hoffmann Ostenhof, O., 1976, Studies on the biosynthesis of cyclitols, XXXV. On the mechanism of action of myo-inositol-1-phosphate synthase from rat testicles. Hoppe Seylers Z. Physiol. Chem. 357: 1667–1671.PubMedGoogle Scholar
  45. Pittner, F., and Hoffmann Ostenhof, O., 1978, Studies on the biosynthesis of cyclitols, XXXVII. On mechanism and function of Schiff’s base formation as an intermediary reaction step of myo-inositol-11-phosphate synthase from rat testicles. Hoppe Seylers Z. Physiol. Chem. 359: 1395–1400.PubMedGoogle Scholar
  46. Raychaudhuri, A., Hait, N.C., Dasgupta, S., Bhaduri, T. J., Deb, R., and Majumder, A.L., 1997, Lmyo-inositol 1-phosphate synthase from plant sources — characteristics of the chloroplastic and cytosolic enzymes. Plant Physiol. 115: 727–736.PubMedGoogle Scholar
  47. Schmidt, D.E., and Westheim, F., 1971, Pk of lysine amino group at active site of acetoacetate decarboxylase. Biochemistry 10: 1249–1253.PubMedCrossRefGoogle Scholar
  48. Sherman, W.R., Rasheed, A., Mauck, L.A., and Wiecko, J., 1977, Incubations of testis myoinositol-1-phosphate synthase with D-(5-18O)glucose 6-phosphate and with H218O show no evidence of Schiff base formation. J. Biol. Chem. 252: 5672–5676.PubMedGoogle Scholar
  49. Stein, A.J., and Geiger, J.H., 2000, Structural studies of MIP synthase. Acta Crystallogr. D 56: 348–350.PubMedCrossRefGoogle Scholar
  50. Stein, A.J., and Geiger, J.H., 2002, The crystal structure and mechanism of 1-L-myo-inositol-1-phosphate synthase. J. Biol. Chem. 277: 9484–9491.PubMedCrossRefGoogle Scholar
  51. Stieglitz, K., Honging, Y., Roberts, M.F., and Stec, B., 2004, Reaching for mechanistic consensus across life kingdoms: Structure and insights into catalysis of the inositol-1-phosphate synthase (mIPS) from Archeoglobus fulgidus. Biochemistry, 44: 213–224.CrossRefGoogle Scholar
  52. Widlanski, T., Bender, S.L., and Knowles, J.R., 1989, Dehydroquinate synthase — a sheep in wolfs clothing. J. Am. Chem. Soc. 111: 2299–2300.CrossRefGoogle Scholar
  53. Wong, Y.H., Mauck, L.A., and Sherman, W.R., 1982, L-Myo-inositol-1-phosphate synthase from bovine testis. Methods Enzymol. 90: 309–314.PubMedCrossRefGoogle Scholar
  54. Wong, Y.H.H., and Sherman, W.R., 1985, Anomeric and other substrate-specificity studies with myo-inositol-1-P synthase. J. Biol. Chem. 260: 1083–1090.Google Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • James H. Geiger
    • 1
  • Xiangshu Jin
    • 1
  1. 1.Chemistry DepartmentMichigan State UniversityEast LansingUSA

Personalised recommendations