The primary focus of our research is the characterization of methylenetetrahydrofolate reductase (MTHFR). This protein is an enzyme that is involved in the generation of the methyl group of methionine in E. coli, humans, and other organisms. MTHFR deficiency in humans can result in homocysteinemia, an autosomal recessive disorder. Homocysteinemia is characterized by varying phenotypes such as developmental delay, motor and gait abnormalities, seizures and psychiatric disturbances. In addition, homocysteinemia has recently been shown to be a significant risk factor for premature cardiovascular disease. In E. coli, the metF gene codes for the MTHFR protein. The E. coli MetF shows significant homology to the N-terminal region of the human MTHFR. Mutations recently identified in humans with MTHFR deficiency occur in regions of high homology with MTHFRs from other species, and these mutations are associated with loss of enzymatic activity. We have, therefore, decided to use the human mutations as a guide to the mutational analysis of the E. coli MetF. Because these mutations occur in evolutionarily conserved regions, insights into requirements for flavin and folate binding, and catalysis of reduction can be obtained by biochemical characterization of the mutant proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31DK009421-01
Application #
2136518
Study Section
Special Emphasis Panel (ZRG3-MEDB (02))
Program Officer
Hyde, James F
Project Start
1996-04-10
Project End
Budget Start
1996-04-01
Budget End
1997-03-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Organized Research Units
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Matthews, R G; Sheppard, C; Goulding, C (1998) Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology. Eur J Pediatr 157 Suppl 2:S54-9