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The Role of Folylpolyglutamates in the Regulation of Folate Metabolism

  • Rowena G. Matthews
  • Jonathan Ross
  • Charles M. Baugh
  • Janine D. Cook
  • Leodis Davis
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 163)

Summary

Folylpolyglutamates have been shown to function as potent inhibitors, relative to the corresponding monoglutamates, of two enzymes involves in the metabolism of methylenetetrahydrofolate (CH2-H4folate) in mammalian tissues. Our initial studies on methylenetetrahydrofolate reductase from pig liver [Matthews, R. G., and Baugh, C. M., Biochemistry, 19, 2040–2045 (1980)] established that this enzyme shows a marked specificity for a hexaglutamyl side chain of both CH2-H4folate substrates and dihydrofolate inhibitors. The Ki values for dihydropteroylpolyglutamate (H2PteGlun) inhibitors decreased from 6.5 μM for the monoglutamate to 0.013 μM for the hexaglutamate and then increased to 0.065 μM for the heptaglutamate. The Iso values for inhibition of the enzyme by H2PteGlun in the presence of 1 μM CH2-H4PteGlun of the same chain length decreased from 7.4 μM for the monoglutamate pair to 0.13 μM for the hexaglutamate pair. We have now shown that methyltetrahydropteroylpolyglutamates (CH3-H4PteGlun) are potent inhibitors of pig liver serine hydroxymethyltransferase. In this case, the decrease in free energy associated with binding of the polyglutamate side chain is expressed not only as an increased affinity of the enzyme for CH3-H4PteGlun derivatives but also as an increased affinity of the enzyme-CH3-H4PteGlun binary complex for glycine. Glycine is bound 33-fold more tightly to the E-CH3-H4PteGlu3 complex than to the E-CH3-H4PteGlu1 complex. Additional glutamyl residues on CH3-H4PteGlun increase the affinity of the enzyme for CH3-H4PteGlun and the heptaglutamyl derivative is the most tightly bound of those studied. In both cases, inhibition by folylpolyglutamates may play a role in regulation of the flux of H4folate-bound one carbon units in vivo. Inhibition of methylene-tetrahydrofolate reductase may occur when cellular levels of H2PteGlun derivatives are elevated, e.g., during administration of methotrexate. Inhibition of serine hydroxymethyltransferase activity in the presence of both CH3-H4PteGlun derivarives and glycine may provide a means of regulating that enzyme by the conjoint concentrations of these two metabolites. Such inhibition may contribute to the rapid onset of megaloblastic anemia following administration of nitrous oxide.

Keywords

Pernicious Anemia Methylenetetrahydrofolate Reductase Double Reciprocal Plot Megaloblastic Anemia Pyridoxal Phosphate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

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Copyright information

© Springer Science+Business Media New York 1983

Authors and Affiliations

  • Rowena G. Matthews
    • 1
  • Jonathan Ross
    • 1
  • Charles M. Baugh
    • 2
  • Janine D. Cook
    • 3
  • Leodis Davis
    • 3
  1. 1.Department of Biological Chemistry and the Biophysics Research DivisionUniversity of MichiganAnn ArborUSA
  2. 2.Department of Biochemistry College of MedicineUniversity of South AlabamaMobileUSA
  3. 3.Department of ChemistryUniversity of IowaIowa CityUSA

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