Biosynthesis of polyglutamates of folates.
Biochem Cell Biol
; 64(7): 667-74, 1986 Jul.
Article
en En
| MEDLINE
| ID: mdl-3756000
Folylpolyglutamate synthetase (FPGS) catalyzes the synthesis of the poly-gamma-glutamate forms of tetrahydrofolate and its co-enzyme adducts, as well as of the folate-analogue drugs. This paper reviews current knowledge of the preparations of FPGS from mammalian sources (rat, hog, mouse, and beef liver). Kinetic constants for the substrates and activators of FPGS are compared. Tetrahydrofolate and 5-formyltetrahydrofolate are excellent substrates for the enzyme. The Km values for the antifolates and their 7-hydroxy metabolites are much higher than those for the tetrahydrofolates. Aminopterin has higher activity with FPGS than does methotrexate, which partially explains its greater toxicity. 5-Formyltetrahydrofolate, which is used as a rescue agent in high-dose methotrexate-rescue chemotherapy, is a better alternate substrate of FPGS than is methotrexate and therefore is a potent competitive inhibitor of the glutamylation of methotrexate. Thus, low concentrations of the rescue agent prevent formation of cytotoxic polyglutamates of methotrexate. The pathway of the reaction is the addition of a glutamate residue to the terminal gamma-carboxyl of the pteridine substrate. That longer folylpolyglutamates are poorer substrates possibly is a result of this addition pathway. Pteroic acid activates FPGS by lowering the Km value of the pteridine substrate. It also greatly increases the activity of the synthetase at physiological pH values.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptido Sintasas
/
Ácidos Pteroilpoliglutámicos
/
Ácido Fólico
Límite:
Animals
Idioma:
En
Revista:
Biochem Cell Biol
Asunto de la revista:
BIOQUIMICA
Año:
1986
Tipo del documento:
Article
Pais de publicación:
Canadá