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Tetrahydropterolypolyglutamate derivatives as substrates of two multifunctional proteins with folate-dependent enzyme activities

Tetrahydropterolypolyglutamate derivatives as substrates of two multifunctional proteins with folate-dependent enzyme activities

Biochimica et Biophysica Acta 611(1): 187-195

Several folate-mediated reactions in eucaryotic cells are carried out by multifunctional proteins using naturally occurring pteroylpolyglutamate derivatives. The compounds tetrahydropteroyl(glutamate)n where n = 1, 3, 5 or 7 were used to determine whether the additional glutamyl residues on the substrates provide kinetic advantages with 2 folate-dependent multifunctional protein. Methylenetetrahydrofolate dehydrogenase(EC cyclohydrolase (EC synthetase (EC, activities comprise a trifunctional protein, and formiminoglutamate:tetrahydrofolate formiminotransferase(EC cyclodeaminase (EC for a bifunctional one. The dehydrogenase, transferase and synthetase had 10 to 40-fold lower Km values for the tetrahydropteroylpolyglutamate derivatives with essentially unchanged values of Vmam. Specificities with cyclodeaminase and cyclohydrolase were determined by using pteroylglutamates as inhibitors of the activities; pteroylpentaglutamate is a 70-fold better inhibitor than folate with cyclodeaminase, but is only 10-fold better with cyclohydrolase. Because of the sequential nature of the enzymic activities in these multifunctional proteins, the tetrahydropteroylpolyglutamate substrates were examined to see if they provide a kinetic advantage, by promoting transfer of folate intermediates between active sites on a single enzyme molecule. With the sequential transferase-deaminase activities, it was observed that the product of the transferase accumulates in the medium with tetrahydropteroylmonoglutamate as the substrate, but does not when the pentaglutamate is used. Chemical modification to selectively inactivate the transferase and deaminase, followed by recombination, demonstrated that this kinetic property is observed because the intermediate formiminotetrahydropteroylpentaglutamate is transferred preferentially to the deaminase site rather than equilibrating with the medium.

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Accession: 068658316

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PMID: 7350916

DOI: 10.1016/0005-2744(80)90054-6

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