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Molecular Pharmacology, Vol 6, 323-334, Copyright © 1970 by the American Society for Pharmacology and Experimental Therapeutics

Folate Reductase of the Amethopterin-Resistant Streptococcus faecium var. durans/Ak

I. Inhibition by Amethopterin and Methasquin, a New Quinazoline Antifolate

ALBERTA M. ALBRECHT 1, DORRIS J. HUTCHISON 1, FRANKLIN K. PEARCE 1, and WILLIAM J. SULING 1

1 Division of Drug Resistance, Sloan-Kettering Institute for Cancer Research, New York, New York 10021

The amethopterin-resistant bacterium Streptococcus faecium var. durans/Ak (SF/Ak) synthesizes at least two species of tetrahydrofolate dehydrogenase. The more abundant species, designated folate reductase, catalyzes the pyridine nucleotide-dependent reductions of folate and dihydrofolate. It has been purified 68-fold and resolved from a minor species. The minor species of enzyme apparently is the specific dihydrofolate reductase, which is prevalent in the amethopterin-sensitive parent strain, S. faecium var. durans/O (SF/O), and mediates only dihydrofolate reduction.

Folate reductase has an estimated molecular weight of 22,500. Like the tetrahydrofolate dehydrogenases of animal sources, it catalyzes dihydrofolate reduction more rapidly than folate reduction. Several kinetic characteristics of folate and dihydrofolate reduction were determined. Similarities between the folate reductase of SF/Ak and the nonbacterial tetrahydrofolate dehydrogenases pointed to the usefulness of this bacterial folate reductase in evaluating the reductase-inhibitory activity of new chemicals synthesized as potential chemotherapeutic agents. Analyses of the inhibition of folate and dihydrofolate reduction by amethopterin and by a new quinazoline antifolate, N-[p-[[(2,4-diamino-5-methyl-6-quinazolinyl)methyl]amino]benzoyl]-L-aspartic acid, designated methasquin, suggested that the latter may be beneficial clinically and, perhaps, more effective than amethopterin. The enzyme-methasquin interaction is slightly firmer than the enzyme-amethopterin interaction and, unlike the latter, is relatively independent of experimental conditions.

Note:
ACKNOWLEDGMENT The authors gratefully acknowledge the statistical assistance of Dr. Isabel M. Mountain.

Submitted on February 28, 1970






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