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Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates.

Abstract
We report the enhanced inhibitory potency of methotrexate (MTX) polyglutamates and dihydrofolate pentaglutamate on the catalytic activity of phosphoribosylaminoimidazolecarboxamide (AICAR) transformylase purified from MCF-7 human breast cancer cells. In the present work, MTX (4-amino-10-methylpteroylglutamic acid) and dihydrofolate, both monoglutamates, were found to be weak competitive inhibitors of AICAR transformylase with Kis of 143 and 63 microM, respectively, and their inhibitory capacity was largely unaffected by the glutamated state of the folate cosubstrate. In contrast, MTX polyglutamates were found to be potent competitive inhibitors, with an approximately 10-fold increase in inhibitory potency with the addition of each glutamate group up to four (i.e., the pentaglutamate derivative). MTX tetra-and pentaglutamates were the most potent, with equivalent Kis of 5.6 X 10(-8) M or 2500-fold more potent than MTX. Dihydrofolate pentaglutamate was as potent an inhibitor as MTX pentaglutamate, with a Ki of 4.3 X 10(-8) M. The potent inhibitory effects demonstrated by the polyglutamate compounds when tested against the folate monoglutamate substrate were sharply curtailed when folate pentaglutamate was used as the substrate. MTX and dihydrofolate pentaglutamates were only 7- and 25-fold more potent than their monoglutamate counterparts under these conditions. A model depicting these complex interactions is postulated. These findings have significant implications regarding the mechanism of action of MTX.
AuthorsC J Allegra, J C Drake, J Jolivet, B A Chabner
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 82 Issue 15 Pg. 4881-5 (Aug 1985) ISSN: 0027-8424 [Print] United States
PMID3860829 (Publication Type: Journal Article)
Chemical References
  • Glutamates
  • Pteroylpolyglutamic Acids
  • Folic Acid
  • Hydroxymethyl and Formyl Transferases
  • Phosphoribosylaminoimidazolecarboxamide Formyltransferase
  • Acyltransferases
  • Methotrexate
Topics
  • Acyltransferases (antagonists & inhibitors, metabolism)
  • Breast Neoplasms (enzymology)
  • Cell Line
  • Female
  • Folic Acid (analogs & derivatives)
  • Glutamates
  • Humans
  • Hydroxymethyl and Formyl Transferases
  • Kinetics
  • Methotrexate (analogs & derivatives, pharmacology)
  • Phosphoribosylaminoimidazolecarboxamide Formyltransferase
  • Pteroylpolyglutamic Acids (pharmacology)
  • Structure-Activity Relationship

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