The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia

Authors

Brian D. Guenther, University of Michigan
Christal A. Sheppard, University of Nebraska-LincolnFollow
Pamela Tran, McGill University
Rima Rozen, McGill University
Rowena G. Matthews, University of MichiganFollow
Martha L. Ludwig, University of MichiganFollow

Date of this Version

4-1999

Citation

Nature Structural Biology 6:4 (April 1999), pp. 359–365; doi: 10.1038/7594

Comments

Copyright © 1999 Nature America Inc. Used by permission.

Abstract

Elevated plasma homocysteine levels are associated with increased risk for cardiovascular disease and neural tube defects in humans. Folate treatment decreases homocysteine levels and dramatically reduces the incidence of neural tube defects. The flavoprotein methylenetetrahydrofolate reductase (MTHFR) is a likely target for these actions of folate. The most common genetic cause of mildly elevated plasma homocysteine in humans is the MTHFR polymorphism A222V (base change C677→T). The X-ray analysis of E. coli MTHFR, reported here, provides a model for the catalytic domain that is shared by all MTHFRs. This domain is a β₈α₈ barrel that binds FAD in a novel fashion. Ala 177, corresponding to Ala 222 in human MTHFR, is near the bottom of the barrel and distant from the FAD. The mutation A177V does not affect K_m or k_cat but instead increases the propensity for bacterial MTHFR to lose its essential flavin cofactor. Folate derivatives protect wild-type and mutant E. coli enzymes against flavin loss, and protect human MTHFR and the A222V mutant against thermal inactivation, suggesting a mechanism by which folate treatment reduces homocysteine levels.