Inhibition of HKSV28 cell growth by 5,11-methenyl-tetrahydrohomofolate

L. J. Slieker, Stephen Benkovic

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

5,11-Methenyl-tetrahydrohomofolate (5,11-methenyl-H4homofolate), a reduced folate analogue, inhibited hamster kidney HKSV28 cells grown in vitro. Hypoxanthine protected the cells from growth inhibition but thymidine had no effect, suggesting that the blockage was in the purine biosynthetic pathway. The measurement of formylglycinamide ribonucleotide levels in the presence of the drug showed that a decrease in these levels was a significant and primary effect of the compound, but the effect had an onset time of approximately 4 hr. In contrast, incubation of the cells with the hydrolysis products 11-formyl-H4/H2homofolate resulted in an immediate decrease in formylglycinamide synthesis. The latter formyl derivatives were shown to be potent competitive inhibitors of glycinamide ribonucleotide transformylase (EC 2.1.2.2) from chicken liver. However, the cell inhibition by 5,11-methenyl-H4homofolate was not confined to glycinamide ribonucleotide transformylase, since the cells were not protected by the presence of aminoimidazole carboxamide. Although aminoimidazole carboxamide ribonucleotide transformylase (EC 2.1.2.3) from chicken liver was not inhibited by these derivatives, we propose that intracellular glutamate elongation of the 11-formyl-H4/H2homofolates might lead to inhibition of both transformylase enzymes.

Original languageEnglish (US)
Pages (from-to)294-302
Number of pages9
JournalMolecular Pharmacology
Volume25
Issue number2
StatePublished - Jan 1 1984

Fingerprint

Phosphoribosylglycinamide Formyltransferase
Hydroxymethyl and Formyl Transferases
Growth
Phosphoribosylaminoimidazolecarboxamide Formyltransferase
Chickens
Aminoimidazole Carboxamide
Hypoxanthine
Liver
Biosynthetic Pathways
Folic Acid
Cricetinae
Thymidine
Glutamic Acid
Hydrolysis
Kidney
Enzymes
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Slieker, L. J. ; Benkovic, Stephen. / Inhibition of HKSV28 cell growth by 5,11-methenyl-tetrahydrohomofolate. In: Molecular Pharmacology. 1984 ; Vol. 25, No. 2. pp. 294-302.
@article{8eb4056e51ec4d2ca5216d077400fe97,
title = "Inhibition of HKSV28 cell growth by 5,11-methenyl-tetrahydrohomofolate",
abstract = "5,11-Methenyl-tetrahydrohomofolate (5,11-methenyl-H4homofolate), a reduced folate analogue, inhibited hamster kidney HKSV28 cells grown in vitro. Hypoxanthine protected the cells from growth inhibition but thymidine had no effect, suggesting that the blockage was in the purine biosynthetic pathway. The measurement of formylglycinamide ribonucleotide levels in the presence of the drug showed that a decrease in these levels was a significant and primary effect of the compound, but the effect had an onset time of approximately 4 hr. In contrast, incubation of the cells with the hydrolysis products 11-formyl-H4/H2homofolate resulted in an immediate decrease in formylglycinamide synthesis. The latter formyl derivatives were shown to be potent competitive inhibitors of glycinamide ribonucleotide transformylase (EC 2.1.2.2) from chicken liver. However, the cell inhibition by 5,11-methenyl-H4homofolate was not confined to glycinamide ribonucleotide transformylase, since the cells were not protected by the presence of aminoimidazole carboxamide. Although aminoimidazole carboxamide ribonucleotide transformylase (EC 2.1.2.3) from chicken liver was not inhibited by these derivatives, we propose that intracellular glutamate elongation of the 11-formyl-H4/H2homofolates might lead to inhibition of both transformylase enzymes.",
author = "Slieker, {L. J.} and Stephen Benkovic",
year = "1984",
month = "1",
day = "1",
language = "English (US)",
volume = "25",
pages = "294--302",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

Slieker, LJ & Benkovic, S 1984, 'Inhibition of HKSV28 cell growth by 5,11-methenyl-tetrahydrohomofolate', Molecular Pharmacology, vol. 25, no. 2, pp. 294-302.

Inhibition of HKSV28 cell growth by 5,11-methenyl-tetrahydrohomofolate. / Slieker, L. J.; Benkovic, Stephen.

In: Molecular Pharmacology, Vol. 25, No. 2, 01.01.1984, p. 294-302.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of HKSV28 cell growth by 5,11-methenyl-tetrahydrohomofolate

AU - Slieker, L. J.

AU - Benkovic, Stephen

PY - 1984/1/1

Y1 - 1984/1/1

N2 - 5,11-Methenyl-tetrahydrohomofolate (5,11-methenyl-H4homofolate), a reduced folate analogue, inhibited hamster kidney HKSV28 cells grown in vitro. Hypoxanthine protected the cells from growth inhibition but thymidine had no effect, suggesting that the blockage was in the purine biosynthetic pathway. The measurement of formylglycinamide ribonucleotide levels in the presence of the drug showed that a decrease in these levels was a significant and primary effect of the compound, but the effect had an onset time of approximately 4 hr. In contrast, incubation of the cells with the hydrolysis products 11-formyl-H4/H2homofolate resulted in an immediate decrease in formylglycinamide synthesis. The latter formyl derivatives were shown to be potent competitive inhibitors of glycinamide ribonucleotide transformylase (EC 2.1.2.2) from chicken liver. However, the cell inhibition by 5,11-methenyl-H4homofolate was not confined to glycinamide ribonucleotide transformylase, since the cells were not protected by the presence of aminoimidazole carboxamide. Although aminoimidazole carboxamide ribonucleotide transformylase (EC 2.1.2.3) from chicken liver was not inhibited by these derivatives, we propose that intracellular glutamate elongation of the 11-formyl-H4/H2homofolates might lead to inhibition of both transformylase enzymes.

AB - 5,11-Methenyl-tetrahydrohomofolate (5,11-methenyl-H4homofolate), a reduced folate analogue, inhibited hamster kidney HKSV28 cells grown in vitro. Hypoxanthine protected the cells from growth inhibition but thymidine had no effect, suggesting that the blockage was in the purine biosynthetic pathway. The measurement of formylglycinamide ribonucleotide levels in the presence of the drug showed that a decrease in these levels was a significant and primary effect of the compound, but the effect had an onset time of approximately 4 hr. In contrast, incubation of the cells with the hydrolysis products 11-formyl-H4/H2homofolate resulted in an immediate decrease in formylglycinamide synthesis. The latter formyl derivatives were shown to be potent competitive inhibitors of glycinamide ribonucleotide transformylase (EC 2.1.2.2) from chicken liver. However, the cell inhibition by 5,11-methenyl-H4homofolate was not confined to glycinamide ribonucleotide transformylase, since the cells were not protected by the presence of aminoimidazole carboxamide. Although aminoimidazole carboxamide ribonucleotide transformylase (EC 2.1.2.3) from chicken liver was not inhibited by these derivatives, we propose that intracellular glutamate elongation of the 11-formyl-H4/H2homofolates might lead to inhibition of both transformylase enzymes.

UR - http://www.scopus.com/inward/record.url?scp=0021345196&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021345196&partnerID=8YFLogxK

M3 - Article

C2 - 6700575

AN - SCOPUS:0021345196

VL - 25

SP - 294

EP - 302

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 2

ER -