Document Detail


Regulation of de novo purine biosynthesis by methenyltetrahydrofolate synthetase in neuroblastoma.
MedLine Citation:
PMID:  16365037     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
5-Formyltetrahydrofolate (5-formylTHF) is the only folate derivative that does not serve as a cofactor in folate-dependent one-carbon metabolism. Two metabolic roles have been ascribed to this folate derivative. It has been proposed to 1) serve as a storage form of folate because it is chemically stable and accumulates in seeds and spores and 2) regulate folate-dependent one-carbon metabolism by inhibiting folate-dependent enzymes, specifically targeting folate-dependent de novo purine biosynthesis. Methenyltetrahydrofolate synthetase (MTHFS) is the only enzyme that metabolizes 5-formylTHF and catalyzes its ATP-dependent conversion to 5,10-methenylTHF. This reaction determines intracellular 5-formylTHF concentrations and converts 5-formylTHF into an enzyme cofactor. The regulation and metabolic role of MTHFS in one-carbon metabolism was investigated in vitro and in human neuroblastoma cells. Steady-state kinetic studies revealed that 10-formylTHF, which exists in chemical equilibrium with 5,10-methenylTHF, acts as a tight binding inhibitor of mouse MTHFS. [6R]-10-formylTHF inhibited MTHFS with a K(i) of 150 nM, and [6R,S]-10-formylTHF triglutamate inhibited MTHFS with a K(i) of 30 nm. MTHFS is the first identified 10-formylTHF tight-binding protein. Isotope tracer studies in neuroblastoma demonstrate that MTHFS enhances de novo purine biosynthesis, indicating that MTHFS-bound 10-formylTHF facilitates de novo purine biosynthesis. Feedback metabolic regulation of MTHFS by 10-formylTHF indicates that 5-formylTHF can only accumulate in the presence of 10-formylTHF, providing the first evidence that 5-formylTHF is a storage form of excess formylated folates in mammalian cells. The sequestration of 10-formylTHF by MTHFS may explain why de novo purine biosynthesis is protected from common disruptions in the folate-dependent one-carbon network.
Authors:
Martha S Field; Doletha M E Szebenyi; Patrick J Stover
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2005-12-19
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  281     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-13     Completed Date:  2006-03-28     Revised Date:  2010-04-12    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4215-21     Citation Subset:  IM    
Affiliation:
Division of Nutritional Sciences, Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites
Carbon-Nitrogen Ligases / antagonists & inhibitors,  chemistry,  physiology*
Cell Line, Tumor
Humans
Mice
Models, Molecular
Neuroblastoma / enzymology*
Purines / biosynthesis*
Substrate Specificity
Grant Support
ID/Acronym/Agency:
HD35687/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Purines; 120-73-0/purine; EC 6.3.-/Carbon-Nitrogen Ligases; EC 6.3.3.2/5,10-methenyltetrahydrofolate synthetase

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