Skip to main content
SpringerLink
Log in

Enzymatic synthesis and function of folylpolyglutamates

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Summary

Derivatives of folic acid occur in nature predominantly as poly (γ-glutamyl) derivatives containing 2–8 glutamate residues. The data regarding the function of these derivatives, and their biosynthesis by eucaryotic and procaryotic folylpolyglutamate synthetases, is reviewed.

The most universal functions of folylpolyglutamates appear to be (a) as the actual cofactors in vivo for folate dependent enzymes, (b) as inhibitors of folate dependent enzymes for which they are not substrates, and (c) to increase retention of folates after they are transported into cells as monoglutamates. Folylpolyglutamates also have numerous specialized functions in specific organisms, e.g. as structural components of some coliphage, and as allosteric regulators in Neurospora crassa.

A single enzyme appears responsible for synthesis of all polyglutamate derivatives, regardless of length. With the recent introduction of sensitive assays this folylpolyglutamate synthetase has begun to be characterized. Although procaryotic and eucaryotic synthetases have many dissimilar properties, both types catalyze the ATP-dependent addition of L-glutamate to the γ-carboxyl of the glutamate present in the folate. Both types also require a monovalent cation and a relatively high pH. The most significant differences between the two types are in their folate substrate specificity and the product lengths derived from various folates.

The mechanism of the bacterial enzyme has been studied and an acyl phosphate intermediate is indicated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Stokstad, E. L. R., 1979. Fed. Proc. 38: 2696–2698.

    Google Scholar 

  2. Blakley, R. L., 1969. Frontiers of Biology Eds. Neuberger, A. & Tatum, E. L. Vol. 13, North-Holland, Amsterdam.

  3. Kutzbach, C. & Stokstad, E. L. R., 1971. Biochim. Biophys. Acta 250: 459–477.

    Google Scholar 

  4. Hoffbrand, A. V., 1975. Prog. in Hematology 9: 85–105.

    Google Scholar 

  5. Baugh, C. M. & Krumdieck, C. L., 1971. Ann. N. Y. Acad. Sci. 186: 7–28.

    Google Scholar 

  6. Scott, J. M. & Weir, D. G., 1976. Clinics in Hematology 5: 547–568.

    Google Scholar 

  7. Covey, J. M., 1980. Life Sciences 26: 665–678.

    Google Scholar 

  8. Nakamura, K. & Kozloff, L. M., 1978. Biochim. Biophys. Acta, 540: 313–319.

    Google Scholar 

  9. Bassett, R., Weir, D. G. & Scott, J., 1976. J. Gen. Microbiol. 93: 169–172.

    Google Scholar 

  10. Curthoys, N. P., Scott, J. M. & Rabinowitz, J. C., 1972. J. Biol. Chem. 247: 1959–1964.

    Google Scholar 

  11. Binkley, S. B., Bird, O. D., Bloom, E. S., Brown, R. A., Calkins, D. G., Campbell, C. J., Emmett, A. D., Pfiffner, J. J., 1944. Science 100: 36–37.

    Google Scholar 

  12. Pfiffner, J. J., Calkins, D. G., Bloom, E. S. & O'Dell, B. L., 1946. J. Am. Chem. Soc. 68: 1392.

    Google Scholar 

  13. Boothe, J. H., Semb, J., Waller, C. W., Angier, R. B., Mowat, J. H., Hutchings, B. L., Stokstad, E. L. R. & SubbaRow, Y., 1949. J. Am. Chem. Soc. 71: 2304–2308.

    Google Scholar 

  14. Semb, J., Boothe, J. H., Angier, R. B., Waller, C. W., Mowat, J. H., Hutchings, B. L. & SubbaRow, Y., 1949. J. Am. Chem. Soc. 71: 2310–2315.

    Google Scholar 

  15. Bird, O. D., Binkley, S. B., Bloom, E. S., Emmett, A. D. & Pfiffner, J. J., 1945. J. Biol. Chem. 157: 413–414.

    Google Scholar 

  16. Gawthorne, J. M. & Smith, R. M., 1973. Biochem. J. 136: 295–301.

    Google Scholar 

  17. Whitehead, V. M., 1973. Clin. Res. 21: 571.

    Google Scholar 

  18. Lavoie, A., Tripp, E., Parsa, K. & Hoffbrand, A. V., 1975. Clin. Sci. Mol. Med. 48: 67–73.

    Google Scholar 

  19. Hoffman, R. M. & Erbe, R. W, 1974. J. Cell Biology 63: 141a.

  20. Moran, R. G., Werkheiser, W. C. & Zakrzewski, S. F., 1976. J. Biol. Chem. 251: 3569–3575.

    Google Scholar 

  21. Sirotnak, F. M., Donati, G. J. & Hutchison, D. J., 1963. J. Bacteriol. 85: 658–665.

    Google Scholar 

  22. Rowe, P. B. & Lewis, G. P., 1973. Biochemistry 12: 1962–1968.

    Google Scholar 

  23. Blakley, R. L. & McDougall, B. M., 1961. J. Biol. Chem. 236: 1163–1167.

    Google Scholar 

  24. Kisliuk, R. L., Gaumont, Y. & Baugh, C. M., 1974. J. Biol. Chem. 249: 4100–4103.

    Google Scholar 

  25. Nath, R. & Greenberg, D. M., 1962. Biochemistry 1: 435–441.

    Google Scholar 

  26. Greenberg, D. M., Tam, B.-D., Jenny, E. & Payes, B., 1966. Biochim. Biophys. Acta 122: 423–435.

    Google Scholar 

  27. Morales, D. R. & Greenberg, D. M., 1964. Biochim. Biophys. Acta 85: 360–376.

    Google Scholar 

  28. Plante, L. T., Crawford, E. J. & Friedkin, M., 1967. J. Biol. Chem. 242: 1466–1476.

    Google Scholar 

  29. Coward, J. K., Parameswaran, K. N., Cashmore, A. R. & Bertino, J. R., 1974. Biochemistry 13: 3899–3903.

    Google Scholar 

  30. Domin, B. A., Cheng, Y.-C. & Hakala, M. T., 1979. Chemistry & Biology of Pterdinies Eds. Kisliuk, R. L. & Brown, G. M., Elsevier-North Holland, New York, pp. 395–399.

  31. Wright, B. E. & Stadtman, T. C., 1956. J. Biol. Chem. 219: 863–871.

    Google Scholar 

  32. Wright, B. E., 1956. J. Biol. Chem. 219: 873–883.

    Google Scholar 

  33. Large, P. J. & Quayle, J. R., 1963. Biochem. J. 87: 386–396.

    Google Scholar 

  34. Uyeda, K. & Rabinowitz, J. C., 1968. Arch. Biochem. Biophys. 123: 271–278.

    Google Scholar 

  35. Salem, A. R., Pattison, J. R. & Foster, M. A., 1972. Biochem. J. 126: 993–1004.

    Google Scholar 

  36. Salem, A. R. & Foster, M. A., 1972. Biochem. J. 127: 845–853.

    Google Scholar 

  37. Blakley, R. L., 1957. Biochem. J. 65: 342–348.

    Google Scholar 

  38. Shane, B. & Stokstad, E. L. R., 1977. J. Gen. Microbiol. 103: 261–270.

    Google Scholar 

  39. Cheng, F. W., Shane, B., Stokstad, E. L. R., 1975. Can. J. Biochem. 53: 1020–1027.

    Google Scholar 

  40. Matthews, R. G. & Baugh, C. M., 1980. Biochemistry 19: 2040–2045.

    Google Scholar 

  41. Guest, J. R. & Jones, K. M., 1960. Biochem. J. 75: 12p-13p.

    Google Scholar 

  42. Whitfield, C. D. & Weissbach, H., 1968. Biochem. Biophys. Res. Common. 33: 996–1003.

    Google Scholar 

  43. Guest, J. R., Friedman, S., Dilworth, M. J. & Woods, D. D., 1964. Ann. N.Y. Acad. Sci. 112: 774–790.

    Google Scholar 

  44. Jones, K. M., Guest, J. R. & Woods, D. D., 1961. Biochem. J. 79: 566–574.

    Google Scholar 

  45. Whitfield, C. D., Steers, E. J., Jr. & Weissbach, H., 1970. J. Biol. Chem. 245: 390–401.

    Google Scholar 

  46. Burton, E., Selhub, J. & Sakami, W., 1969. Biochem. J. 111: 793–795.

    Google Scholar 

  47. Morningstar, J. F., Jr. & Kisliuk, R. L., 1965. J. Gen. Microbiol. 39: 43–51.

    Google Scholar 

  48. Cauthen, S. E., Foster, M. A. & Woods, D. D., 1966. Biochem. J. 98: 630–635.

    Google Scholar 

  49. Wang, F. K., Koch, J. & Stokstad, E. L. R., 1967. Biochemische Z. 346: 458–466.

    Google Scholar 

  50. Burton, E. G. & Sakami, W., 1969. Biochem. Biophys. Res. Commun. 36: 228–234.

    Google Scholar 

  51. Coward, J. K., Chello, P. L., Cashmore, A. R., Parameswaran, K. N., DeAngelis, L. M. & Bertino, J. R., 1975. Biochemistry 14: 1548–1552.

    Google Scholar 

  52. Loughlin, R. E., Elford, H. L. & Buchanan, J. M., 1964. J. Biol. Chem. 239: 2888–2895.

    Google Scholar 

  53. Uyeda, K. & Rabinowitz, J. C., 1967. J. Biol. Chem. 242: 4378–4385.

    Google Scholar 

  54. Yeh, Y.-C. & Greenberg, D. M., 1965. Biochim. Biophys. Acta 105: 279–291.

    Google Scholar 

  55. MacKenzie, R. E. & Baugh, C. M., 1980. Biochim. Biophys. Acta 611: 187–195.

    Google Scholar 

  56. MacKenzie, R. E., 1973. Biochem. Biophys. Res. Common. 53: 1088–1095.

    Google Scholar 

  57. Paukert, J. L., Straus, L. D. & Rabinowitz, J. C., 1976. J. Biol. Chem. 251: 5104–5111.

    Google Scholar 

  58. Himes, R. H. & Rabinowitz, J. C., 1962. J. Biol. Chem. 237: 2903–2914.

    Google Scholar 

  59. Curthoys, N. P. & Rabinowitz, J. C., 1972. J. Biol. Chem. 247: 1965–1971.

    Google Scholar 

  60. Powers, S. G. & Snell, E. E., 1976. J. Biol. Chem. 251: 3876–3793.

    Google Scholar 

  61. Jaenicke, L. & Brode, E., 1961. Biochemisches Z. 334: 108–132.

    Google Scholar 

  62. Brode, E. & Jaenicke, L., 1961. Biochemisches Z. 334: 328–341.

    Google Scholar 

  63. Jaenicke, L. & Brode, E., 1961. Biochemisches Z. 334: 342–356.

    Google Scholar 

  64. Lewis, G. P., Salem, M. E. & Rowe, P. B., 1979. Chemistry and Biology of Pteridines Eds. Kisliuk, R. L. & Brown, G. M., Elsevier-North Holland, New York, pp. 441–442.

  65. Kisliuk, R. L., Gaumont, Y., Baugh, C. M., Galivan, J., Maley, F. & Maley, G. F., 1978. Fed. Proc. 37: 1427.

    Google Scholar 

  66. Galivan, J. H., Maley, F. & Baugh, C. M., 1976. Biochem. Biophys. Res. Common. 71: 527–534.

    Google Scholar 

  67. Dolnick, B. J. & Cheng, Y.-C., 1978. J. Biol. Chem. 253: 3563–3567.

    Google Scholar 

  68. Baggott, J. E. & Krumdieck, C. L., 1979. Biochemistry 18: 1036–1041.

    Google Scholar 

  69. Slavik, K., Zizkovsky, V., Slavikova, V. & Fort, P., 1974. Biochem. Biophys. Res. Commun. 59: 1173–1184.

    Google Scholar 

  70. Rabinowitz, J. C. & Himes, R. H., 1960. Fed. Proc. 19: 963–970.

    Google Scholar 

  71. Uyeda, K. & Rabinowitz, J. C., 1967. J. Biol. Chem. 242: 24–31.

    Google Scholar 

  72. Gaertner, F. H., 1978. Trends Biochem. Sci. (March): 63–65.

  73. Kirschner, K. & Bisswanger, H., 1976. Annu. Rev. Biochem. 45: 143–166.

    Google Scholar 

  74. Delk, A. S., Nagle, D. P., Jr. & Rabinowitz, J. C., 1980. J. Biol. Chem. 255: 4387–4390.

    Google Scholar 

  75. Cohen, L. & MacKenzie, R. E., 1978. Biochim. Biophys. Acta 522: 311–317.

    Google Scholar 

  76. Shane, B. & Stokstad, E. L. R., 1976. J. Biol. Chem. 251: 3405–3410.

    Google Scholar 

  77. Nixon, P. F., Slutsky, G., Nahas, A. & Bertino, J. R., 1973. J. Biol. Chem. 248: 5932–5936.

    Google Scholar 

  78. McBurney, M. W. & Whitmore, G. F., 1974. Cell 2: 173–182.

    Google Scholar 

  79. Friedkin, M., Plante, L. T., Crawford, E. J. & Crumm, M., 1975. J. Biol. Chem. 250: 5614–5621.

    Google Scholar 

  80. Friedkin, M., Crawford, E. J., Donovan, E. & Pastore, E. J., 1962. J. Biol. Chem. 237: 3811–3814.

    Google Scholar 

  81. Kisliuk, R. L., Gaumont, Y., Baugh, C. M., Galivan, J., Maley, G. F. & Maley, F., 1979. Chemistry and Biology of Pteridines (Kisliuk, R. L. & Brown, G. M., eds.) Elsevier North Holland, New York, pp. 431–435.

  82. Maley, G. F. & Maley, F. & Baugh, C. M., 1979. J. Biol. Chem. 254: 7485–7487.

    Google Scholar 

  83. Schirch, L. & Ropp, M., 1967. Biochemistry 6: 253–257.

    Google Scholar 

  84. Krumdieck, C. L., Cornwell, P. E., Thompson, R. W. & White, W. E., Jr., 1977. Folic Acid. Biochemistry and Physiology in Relation to the Human Nutrition Requirement. National Academy of Sciences, Washington, D.C., pp. 25–42.

    Google Scholar 

  85. Bertino, J. R. & Hillcoat, B. L., 1968. Adv. Enz. Regulation 6: 335–349.

    Google Scholar 

  86. Buehring, K. U., Tamura, T. & Stokstad, E. L. R., 1974. J. Biol. Chem. 249: 1081–1089.

    Google Scholar 

  87. Shane, B. & Stokstad, E. L. R., 1975. J. Biol. Chem. 250: 2243–2253.

    Google Scholar 

  88. Shane, B., 1980. J. Biol. Chem. 255: 5649–5654.

    Google Scholar 

  89. Nair, M. G. & Baugh, C. M., 1973. Biochemistry 12: 3923–3927.

    Google Scholar 

  90. Nahas, A., Nixon, P. F. & Bertino, J. R., 1972. Cancer Res. 32: 1416–1421.

    Google Scholar 

  91. Goldman, I. D., 1971. Ann. N.Y. Acad. Sci. 186: 400–422.

    Google Scholar 

  92. Hoffbrand, A. V., Tripp, E., Houlihan, C. M. & Scott, J. M., 1973. Blood 42: 141–146.

    Google Scholar 

  93. Galivan, J., 1979. Cancer Res. 39: 735–743.

    Google Scholar 

  94. Taylor, R. T. & Hanna, M. L., 1977. Arch. Biochem. Biophys. 181: 331–344.

    Google Scholar 

  95. Sirotnak, F. M., Chello, P. L., Piper, J. R. & Montgomery, J. A., 1978. Biochem. Pharm. 27: 1821–1825.

    Google Scholar 

  96. Tamura, T., Shin, Y.-S., Williams, M. A. & Stokstad, E. L. R., 1972. Anal. Biochem. 49: 517–521.

    Google Scholar 

  97. Baugh, C. M., Stevens, J. C. & Krumdieck, C. L., 1970. Biochim. Biophys. Acta 212: 116–125.

    Google Scholar 

  98. Kozloff, L. M., 1980. BioSystems 12: 239–247.

    Google Scholar 

  99. Zamierowski, M. M. & Wagner, C., 1977. J. Biol. Chem. 252: 933–938.

    Google Scholar 

  100. Wittwer, A. J. & Wagner, C., 1979. Fed. Proc. 38: 393.

    Google Scholar 

  101. Wittwer, A. J. & Wagner, C., 1980. Proc. Natl. Acad. Sci. USA 77: 4484–4488.

    Google Scholar 

  102. Kallen, R. G. & Jencks, W. P., 1966. J. Biol. Chem. 241: 5851–5863.

    Google Scholar 

  103. Piper, W. N. & Tephly, T. R., 1974. Life Sciences 14: 873–876.

    Google Scholar 

  104. Piper, W. N. & Van Lier, R. B. L., 1977. Mol. Pharm. 13:1126–1135.

    Google Scholar 

  105. Piper, W. N., Van Lier, R. B. L. & Hardwicke, D. M., 1979. In: Chemistry and Biology of Pteridines (Kisliuk, R. L. & Brown, G. M., eds.) Elsevier-North Holland, New York, pp. 329–334.

  106. Galivan, J., Maley, F. & Baugh, C. M., 1977. Arch. Biochem. Biophys. 184: 346–354.

    Google Scholar 

  107. Selhub, J., Savin, M. A., Sakami, W. & Flavin, M., 1971. Proc. Nat. Acad. Sci. USA 68: 312–314.

    Google Scholar 

  108. Shane, B., 1980. J. Biol. Chem. 255: 5655–5662.

    Google Scholar 

  109. McGuire, J. J., Kitamoto, Y., Hsieh, P., Coward, J. K. & Bertino, J. R., 1979. In: Chemistry and Biology of Pteridines (Kisliuk, R. L. & Brown, G. M., eds.) Elsevier-North Holland, New York, pp. 471–476.

  110. Richardson, R. E., Healy, M. J. & Nixon, P. F., 1979. Biochim. Biophys. Acta 585: 128–133.

    Google Scholar 

  111. Taylor, R. T. & Hanna, M. L., 1979. Arch. Biochem. Biophys. 197: 36–43.

    Google Scholar 

  112. McGuire, J. J., Hsieh, P., Coward, J. K. & Bertino, J. R., 1980. J. Biol. Chem. 255: 5776–5788.

    Google Scholar 

  113. Ritari, S. J., Sakami, W., Black, C. W. & Rzepka, J., 1973. Neurospora Newsletter 20: 26–27.

    Google Scholar 

  114. Ritari, S. J., Sakami, W. & Black, C. W., 1973. Neurospora Newsletter 20: 27.

    Google Scholar 

  115. Masurekar, M. & Brown, G. M., 1975. Biochemistry 11: 2424–2430.

    Google Scholar 

  116. Griffin, M. J. & Brown, G. M., 1964. J. Biol. Chem. 239: 310–316.

    Google Scholar 

  117. Shin, Y.-S., Williams, M. A. & Stokstad, E. L. R., 1972. Biochem. Biophys. Res. Commun. 47: 35–43.

    Google Scholar 

  118. Houlihan, C. M. & Scott, J. M., 1972. Biochem. Biophys. Res. Commun. 48: 1675–1681.

    Google Scholar 

  119. Leslie, G. I. & Baugh, C. M., 1974. Biochemistry 13: 4957–4961.

    Google Scholar 

  120. Kamen, B. A. & Caston, J. D., 1975. J. Biol. Chem. 250: 2203–2205.

    Google Scholar 

  121. Shin, Y.-S., Chan, C., Vidal, A. J., Brody, T. & Stokstad, E. L. R., 1976. Biochim. Biophys. Acta 444: 794–801.

    Google Scholar 

  122. Fridovich, L, 1974. Life Sciences 14: 819–826.

    Google Scholar 

  123. Taylor, R. T., Hanna, M. L., Jones,C. & Kao, F.-T., 1980. Fed. Proc. 39: 655.

    Google Scholar 

  124. Ritari, S. J., Sakami, W., Black, C. W. & Rzepka, J., 1975. Anal. Biochem. 63: 118–129.

    Google Scholar 

  125. Brody, T., 1976. Federation Proc. 35: 1344.

    Google Scholar 

  126. Lewis, G. P. & Rowe, P. B., 1979. Anal. Biochem. 93: 91–97.

    Google Scholar 

  127. Baugh, C. M., Braverman, E. B., Nair, M. G., Horne, D. W., Briggs, W. T. & Wagner, C., 1979. Anal. Biochem. 92: 366–369.

    Google Scholar 

  128. Evans, H. J. & Sorger, G. J., 1966. Annu. Rev. Plant Physiol. 17: 47–76.

    Google Scholar 

  129. Suelter, C. H., 1970. Science 168: 789–795.

    Google Scholar 

  130. Himes, R. H. & Harmony, J. A. K., 1973. CRC Crit. Rev. Biochem. 1: 501–535.

    Google Scholar 

  131. Sakami, W., Ritari, S. J., Black, C. W. & Rzepka, J., 1973. Fed. Proc. 32: 471.

    Google Scholar 

  132. Gawthorne, J. M. & Smith, R. M., 1974. Biochem. J. 142: 119–126.

    Google Scholar 

  133. Shane, B., 1980. J. Biol. Chem. 255: 5663–5667.

    Google Scholar 

  134. Moran, R. G. & Colman, P. D., 1980. Proc. Am. Assoc. Cancer Res. 21: 25.

    Google Scholar 

  135. Brody, T. & Stokstad, E. L. R., 1979. In: Folic Acid in Neurology, Psychiatry, and Internal Medicine (Botez, M. I. & Reynolds, E. H., eds.) Raven Press, New York, pp. 55–62.

  136. Spronk, A. M., 1973. Fed. Proc. 32: 471.

    Google Scholar 

  137. McGuire, J. J., Hsieh, P., Coward, J. K. & Bertino, J. R., 1980. Fed. Proc. 39: 1699.

    Google Scholar 

  138. Shane, B., Brody, T. & Stokstad, E. L. R., 1979. In: Chemistry and Biology of Pteridines (Kisliuk, R. L. & Brown, G. M., eds.) Elsevier-North Holland, New York, pp. 341–346.

  139. Bassett, R., Weir, D. & Scott, J., 1976. Biochem. Soc. Trans. 4: 500–502.

    Google Scholar 

  140. Caperelli, C. A., Benkovic, P. A., Chettur, G. & Benkovic, S. J., 1980. J. Biol. Chem. 255: 1885–1890.

    Google Scholar 

  141. White, J. C., Bailey, B. D. & Goldman, I. D., 1978. J. Biol. Chem. 253: 242–245.

    Google Scholar 

  142. Sirotnak, F. M., Chello, P. L., Moccio, D. M., Kisliuk, R. L., Compebine, G., Gaumont, Y. & Montgomery, J. A., 1979. Biochem. Pharm. 28: 2993–2997.

    Google Scholar 

  143. Scott, V. F. & Donaldson, K. O., 1964. Biochem. Biophys. Res. Commun. 14: 523–526.

    Google Scholar 

  144. Shane, B. & Stokstad, E. L. R., 1977. J. Gen. Microbiol. 103: 249–259.

    Google Scholar 

  145. Acharya, S. P. & Hynes, J. B., 1975. J. Heterocycl. Chem. 12: 1283–1286.

    Google Scholar 

  146. Rader, J. I. & Huennekens, F. M., 1973. In: The Enzymes (Boyer, P. D., ed.) 3rd edition, v. 9, pp. 197–223.

Download references

Author information

Authors and Affiliations

  1. Dept. of Pharmacology, Yale University School of Medicine, 06510, New Haven, CT, USA

    John J. McGuire & Joseph R. Bertino

Authors
  1. John J. McGuire
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph R. Bertino
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

McGuire, J.J., Bertino, J.R. Enzymatic synthesis and function of folylpolyglutamates. Mol Cell Biochem 38, 19–48 (1981). https://doi.org/10.1007/BF00235686

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00235686

Keywords

Search

Navigation