| Folate analogues as substrates of mammalian folylpolyglutamate synthetase. | |
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MedLine Citation:
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PMID: 3873989 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The antifolate drugs methotrexate (MTX) and aminopterin (AM) have been tested as substrates for folylpolyglutamate synthetase (FPGS) partially purified from beef liver. The Km for MTX is 100 microM, and that for AM is 25 microM. These values are considerably higher than those for either tetrahydrofolate or folinic acid. Based on their ratios of Vmax to Km, AM is a better substrate than is MTX for the beef liver FPGS. Both are poorer substrates than tetrahydrofolate. The 7-hydroxy metabolites of MTX and AM also are substrates for FPGS. The reactivity of 7-hydroxymethotrexate is similar to that of MTX, but 7-hydroxyaminopterin is a poorer substrate than AM. Folinic acid, often used as the rescue agent in high-dose MTX therapy, has a low Km with mammalian FPGS (7 microM). Its activity is comparable to that of the best substrate, tetrahydrofolate. Low concentrations of folinic acid prevent the formation of polyglutamates of MTX. This inhibition is competitive, presumably because folinic acid and MTX are competing substrates for FPGS. The activities of folate and antifolate substrates also have been determined with rat liver FPGS. With near-saturating concentrations of AM, MTX, or 7-hydroxymethotrexate, the reaction velocity exceeds that with an optimal concentration of tetrahydrofolate. However, the Km values of the folate analogues all are greater than those of the tetrahydrofolate coenzymes. In contrast to the formation of long-chain polyglutamates observed when tetrahydrofolate or folinic acid was the substrate, beef liver FPGS, under our reaction conditions, cannot catalyze the formation from MTX monoglutamate of polyglutamates longer than the triglutamate. MTX di- and triglutamates are poorer substrates than is MTX itself. Longer polyglutamates of MTX, while having no activity as substrates, must bind to the enzyme, because they are inhibitors. Our observations using MTX and AM with the enzymatic FPGS system help to rationalize the therapeutic use of antifolates. |
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Authors:
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M M Schoo; Z B Pristupa; P J Vickers; K G Scrimgeour |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cancer research Volume: 45 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 1985 Jul |
Date Detail:
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Created Date: 1985-08-09 Completed Date: 1985-08-09 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 3034-41 Citation Subset: IM |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aminopterin
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metabolism Animals Cattle Folic Acid Antagonists / metabolism*, therapeutic use Kinetics Leucovorin / metabolism Methotrexate / metabolism Peptide Synthases / analysis*, antagonists & inhibitors |
| Chemical | |
Reg. No./Substance:
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0/Folic Acid Antagonists; 54-62-6/Aminopterin; 58-05-9/Leucovorin; 59-05-2/Methotrexate; EC 6.3.2.-/Peptide Synthases; EC 6.3.2.17/folylpolyglutamate synthetase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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