Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 458, Issue 2, Pages 194-201Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2006.12.023
Keywords
methenyltetrahydrofolate synthetase; folate; one-carbon metabolism; homofolate; antifolate
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Funding
- NICHD NIH HHS [HD35687, R01 HD035687] Funding Source: Medline
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The interaction of 5-formyltetrahydrofolate analogs with murine methenyltetrahydrofolate synthetase (MTHFS) was investigated using steady-state kinetics, molecular modeling, and site-directed mutagenesis. MTHFS catalyzes the irreversible cyclization of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate. Folate analogs that cannot undergo the rate-limiting step in catalysis were inhibitors of murine MTHFS. 5-Formyltetrahydrohomofolate was an effective inhibitor of murine MTHFS (K-i = 0.7 mu M), whereas 5-formyl, 10-methyltetrahydrofolate was a weak inhibitor (K-i = 10 mu M). The former, but not the latter, was slowly phosphorylated by MTHFS. 5-Formyltetrahydrohomofolate was not a substrate for murine MTHFS, but was metabolized when the MTHFS active site Y151 was mutated to Ala. MTHFS active site residues do not directly facilitate N10 attack on the on the N5-iminium phosphate intermediate, but rather restrict N10 motion around N5. Inhibitors specifically designed to block N10 attack appear to be less effective than the natural 10-formyltetrahydrofolate polyglutamate inhibitors. (c) 2006 Elsevier Inc. All rights reserved.
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