Areas of Interest
Our laboratory studies the mechanisms of enzymes that use folic acid and vitamin B12 (cobalamin) as cofactors. I became interested in this research area when I began teaching medical students about one carbon metabolism, and realized that although tetrahydrofolate and dihydroflavin cofactors have very similar structures, they are involved in highly dissimilar reactions. Recent studies have focused on two enzymes: cobalamin-dependent methionine synthase and methylenetetrahydrofolate reductase. Methionine synthase is one of two B12-dependent enzymes in humans; impairment of its activity leads to the classic symptoms of vitamin 12 deficiency, megaloblastic anemia and a characteristic neuropathy of the spinal cord. The enzyme consists of a single large polypeptide, and the reaction mechanism requires that several different substrates be brought sequentially into contact with the cobalamin prosthetic group, which is alternately methylated and demethylated. Our laboratory is studying the way in which this complicated reaction is staged by the protein. In a collaboration with the laboratory of Professor Martha Ludwig, the structure of individual domains of methionine synthase is being determined by x-ray crystallography. Methylenetetrahydrofolate reductase catalyzes the formation of the methyl donor for methionine synthase, methyltetrahydrofolate. Our laboratory first purified this enzyme to homogeneity from porcine liver and obtained peptide sequence data. In a collaboration with Dr. Rima Rozen at McGill University, the cDNA encoding the human enzyme has now been cloned and characterized. It has been shown that a polymorphism in the human enzyme, present in 12% of the population, leads to elevated concentrations of homocysteine in the blood. Elevated plasma homocysteine levels have recently been shown to be a major risk factor for cardiovascular disease, and folic acid has been shown to lower homocysteine levels in humans. The methylenetetrahydrofolate reductase polymorphism is the most common cause of mild elevations in plasma homocysteine. Recent studies in our laboratory have elucidated the molecular phenotype associated with the methylenetetrahydrofolate reductase polymorphism, which leads to dissociation of the flavin cofactor and loss of activity. In collaboration with Dr. Ludwig, an x-ray structure of the bacterial methylenetetrahydrofolate reductase has been determined.
A second area of interest is the use of proteomics and genomics to study global regulation in prokaryotes. We collaborate with Bob Blumenthal at the Medical College of Ohio and Ruth VanBogelen at Warner-Lambert Parke-Davis to use a combination of two-dimensional gel electrophoresis and mass spectrometry to identify proteins that are regulated by the leucine-responsive regulatory protein (Lrp). We now plan to use array technology to identify genes that are under the control of Lrp.
Honors & Awards
2005 Fellow, American Academy of Arts & Sciences
2004 Member, Institute of Medicine
2003 Henry Russel Lectureship, University of Michigan
2002 Fellow, National Academy of Sciences
2002 Fellow, American Academy of Microbiology
2001 Repligen Award, American Chemical Society
2000 William C. Rose Award, American Society for Biochemistry and Molecular Biology
1998 Fellow, American Association for the Advancement of Science
1997-2001 Senior Fellow, Michigan Society of Fellows
1997 Distinguished Faculty Achievement Award, University of Michigan
1995 G. Robert Greenberg Distinguished University Professorship, University of Michigan
1994 Distinguished Faculty Lectureship in Biomedical Research, University of Michigan
A love affair with vitamins.
J Biol Chem. 2009; 284: 26217-28.
Insights into the reactivation of cobalamin-dependent methionine synthase.
Koutmos M, Datta S, Pattridge KA, Smith JL, Matthews RG.
Proc Natl Acad Sci U S A. 2009; 106: 18527-32.
Oxidation of cysteine 645 of cobalamin-independent methionine synthase causes a methionine limitation in Escherichia coli.
Hondorp ER, Matthews RG.
J Bacteriol. 2009; 191: 3407-10.
Cobalamin- and corrinoid-dependent enzymes.
Met Ions Life Sci. 2009; 6: 53-114.
Cobalamin-dependent and cobamide-dependent methyltransferases.
Matthews RG, Koutmos M, Datta S.
Curr Opin Struct Biol. 2008; 18: 658-66.
For a list of publications from PubMed, click HERE