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J. Biol. Chem., Vol. 255, Issue 12, 5776-5788, 06, 1980
JJ McGuire, P Hsieh, JK Coward and JR Bertino
Rat liver folylpolyglutamate synthetase was partially purified and its
reaction and products were characterized. The preparation contained no
conjugase activity. Gel filtration analysis revealed a molecular weight of
69,000. The synthetase was optimally active at pH 8.4 (37 degrees C),
required mercaptoethanol and a monovalent cation, and was highly specific
for L-glutamate. Only purine nucleoside triphosphates served as the energy
source for the reaction; ATP and dATP gave the best activity. All naturally
occurring folates (including 5-methyl- tetrahydrofolic acid) as well as a
number of folate analogs (including methotrexate) served as substrates. The
unnatural diastereoisomer of at least one folate, 5,6,7,8-tetrahydrofolic
acid, was also a substrate. Modifications of the terminal, acceptor
glutamate led to loss of substrate activity, as well as loss of binding.
High pressure liquid chromatography analysis, conjugase digestion, double
radiolabel studies, and amino acid analysis of acid-hydrolyzed product
confirmed that folylpoly-gamma-glutamates were synthesized. High
concentrations of (dl)-5,6,7,8-tetrahydrofolic acid favored accumulation of
short chain (predominantly diglutamate) products while low concentrations
favored accumulation of longer chains (predominantly tetraglutamate). This
inverse relationship between concentration and chain length may be of
regulatory significance. Synthesis of pentaglutamate forms, the predominant
chain length of rat liver folates in vivo, was detected at low
(dl)-5,6,7,8-tetrahydrofolic acid, but hexaglutamate was not detected.
Synthetic (l)-5,6,7,8-tetrahydropteroylpentaglutamate was a poor substrate
for the synthetase but it inhibited formation of polyglutamates from
monoglutamates. These observations indicate that the predominant chain
length of folates in rat liver may be determined solely by the substrate
specificity of the rat liver synthetase. Inhibition by the specificity of
the rat liver synthetase. Inhibition by the pentaglutamate derivative
offers a means by which folylpolyglutamates could regulate their own
synthesis.
Enzymatic synthesis of folylpolyglutamates. Characterization of the reaction and its products
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