Synthesis of (6R,11S)- and (6R,11R)-5,10-Methylene[11-1H2H]tetrahydrofolate. Stereochemical Paths of Serine Hydroxymethyltransferase, 5,10-Methylenetetrahydrofolate Dehydrogenase, and Thymidylate Synthetase Catalysis

Lawrence J. Slieker, Stephen J. Benkovic

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Abstract

The stereochemical courses of the reactions catalyzed by serine hydroxymethyltransferase (EC 2.1.2.1) and 5,10-methylenetetrahydrofolate dehydrogenase (EC 1.5.1.5) have been determined. The method employed was to prepare the labeled intermediates (6R,11R)- and (6R,11R)-5,10-methylene[l l-1H,2H]tetrahydrofolate by stereospecific chemical reduction and to determine their absolute stereochemistry at Cl 1 by the measurement of proton nuclear Overhauser enhancements (NOE's). Correlation of these results with those obtained by generating (6R)-5,10-methylene[l l-1H,2H]tetrahydrofolate enzymatically from (3S)- and (3R)-[3-1H,2H]serine with the transferase and from (6R)-5,10-methenyl[ll-2H]tetrahydrofolate via the dehydrogenase delineated the stereochemical paths of both enzymes. Serine hydroxymethyltransferase converts (3S)- and (35)-[3-1H,2H]serine to (65,1 15)- and (6R,11R)-5,10-methylene[l l-1H,2H]tetrahydrofolate, respectively, and the dehydrogenase stereospecifically removes HR. These results also were correlated with those obtained by Tatum et al. [Tatum, C. M.; Vederas, J.; Schleicher, E.; Benkovic, S. J.; Floss, H. G. J. Chem. Soc. Chem. Commun. 1977, 218–220] on thymidylate synthetase (EC 2.1.1.b) to further delineate the stereochemical course of the one carbon unit transfer and accompanying reduction catalyzed by that enzyme.

Original languageEnglish (US)
Pages (from-to)1833-1838
Number of pages6
JournalJournal of the American Chemical Society
Volume106
Issue number6
DOIs
StatePublished - Mar 1 1984

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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