Analogues of folic acid and the activity of dihydrofolic acids in the synthesis of methionine by Escherichia coli

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Abstract
Dihydropteroylmonoglutamate and dihydropteroyl-triglutamate resembled the corresponding tetrahydro-derivatives in their ability to serve as cofactors for the synthesis of methionine from serine and homocysteine by extracts of Escherichia coli PA 15. Cobalamin was a necessary component of the reaction mixture only if the pteroylmonoglutamates were the cofactors for C1 transfer. A flavin coenzyme was required for best synthesis of methionine with some preparations of the extract and, with dihydrofolates as cofactor, TPN was also necessary. Dihydropteroylmonoglutamate also resembled the tetrahydro-derivative in inhibiting methionine formation when the folic acid cofactor was supplied by an extract of heated E. coli; the inhibition was overcome by cobalamin. Aminopterin and amethopterin prevented both the cofactor and inhibitory activities of the dihydrofolates; the activities of the tetrahydrofolates, even when present only in catalytic quantities, were unaffected by these analogues. In addition to the above evidence the characterization of an aminopterin-sensitive dihydrofolate reductase in these bacterial extracts supported the view that the dihydro-compounds were active only after conversion into the tetrahydro-compounds. Aminopterin also prevented the utilization of formaldehyde as a source of the methyl group of methionine when dihydropteroylmonoglutamate, though not tetrahydropteroylmono-glutamate, was the cofactor for the C1 transfer. Under conditions similar to those used for the synthesis of methionine both dihydro- and tetrahydro-pteroylmonoglutamate acted as cofactors for serine trans-hydroxymethylase; aminopterin inhibited the activity only of the dihydro-derivative. It is concluded provisionally that dihydropteroylglutamate is not liberated during the reduction of the hydroxymethyl group of serine to the methyl group of methionine by E. coli.