Rowena Matthews, Ph.D.

Professor Emeritus, Biological Chemistry
G. Robert Greenberg Distinguished University Professor, Biological Chemistry

Life Sciences Institute

Ofc: 4002

Ann Arbor, MI. 48109-2216

 

(734) 764-9459

Appointments

Biological Chemistry, Medical School

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

1997-2001 Senior Fellow, Michigan Society of Fellows
1997 Distinguished Faculty Achievement Award
1994 Distinguished Faculty Lectureship in Biomedical Research
1995 G. Robert Greenberg Distinguished University Prof
1994 Distinguished Biomedical Lecturer
1998 Fellow, Am Association for the Advance of Science
2000 W C Rose Award, ASBMB
2001 Repligen Award, ACS, Div. BioChem
2002 Fellow, American Academy of Microbiology
2002 Fellow, National Academy of Sciences
2003 Henry Russel Lectureship
2004 Member, Institute of Medicine
2005 Elected Fellow Am Academy of Arts & Sciences

Published Articles or Reviews

Drennan, C. L., Huang, S., Drummond, J. T., Matthews, R. G., and Ludwig, M. L. (1994) How a Protein Binds B12: A 3.0 *X-ray Structure of the B12-Binding Domains of Methionine Synthase. Science 266:1669-1674.

Goyette, P., Sumner, J. P., Milos, R., Duncan, A. M. V., Rosenblatt, D. S., Matthews, R. G., and Rozen, R. (l994) Human Methylenetetrahydrofolate Reductase: Isolation of cDNA, Mapping and Mutation Identification. Nature Genetics 7:195-200. PMID: 7920641

Frosst, P., Blom, H. J., Milos, R., Goyette, P., Sheppard, C. A., Matthews, R. G., Boers, G. J. H., den Heijer, M., Kluijtmans, L. A. J., van den Heuvel, L. P., and Rozen, R. (1995) A candidate genetic risk factor for vascular disease: A common mutation at the methylenetetrahydrofolate reductase locus. Nature Genetics 10, 111-113.

Goulding, C. W., Postigo, D., and Matthews, R. G. (l997) Cobalamin-dependent methionine synthase is a modular protein with distinct regions for binding homocysteine, methyltetrahydrofolate, cobalamin, and adenosylmethionine. Biochemistry 36, 8082-8091. PMID: 9201956

Goulding, C. W., and Matthews, R. G. (l997) Cobalamin-dependent methionine synthase from Escherichia coli: involvement of zinc in homocysteine activation. Biochemistry 36, 15749-15757. PMID: 9398304

Ludwig, M. L., and Matthews, R. G. (l997) B12 (cobalamin)-dependent enzymes. Annual Review of Biochemistry 66, 269-313.

Bhagwat, S., Rice, M. R., Matthews, R. G., and Blumenthal, R. M. (l997) Use of an inducible regulatory protein to identify members of a regulon: application to the regulon controlled by the leucine-responsive regulatory protein (Lrp) in Escherichia coli. J. Bacteriol. 179, 6254-6263. PMID: 9335270

Guenther, B. D., Sheppard, C. A., Tran, P., Rozen, R., Matthews, R. G., and Ludwig, M. L. (l999) The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli: a model for the role of folate in ameliorating hyperhomocysteinemia in humans. Nature Structural Biology, 6, 359-365.

VanBogelen, R. A., Greis, K. D., Blumenthal, R. M., Tani, T. H., and Matthews, R. G. (l999) Mapping regulatory networks in microbial cells. Trends Microbiol. 7, 1540-1546.
Bandarian, V., and Matthews, R. G. (2001) Quantitation of rate enhancements obtained by binding of cobalamin to methionine synthase. Biochemistry 40, 5056-5064.

Matthews, R. G. (2001) Cobalamin-dependent methyltransferases. Accounts of Chemical Research 34, 681-689.

Yamada, K., and Matthews, R. G. (2001) Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc. Natl. Acad. Sci., USA, 98, 14853-14858. PMID: 11742092

Bandarian, V., Pattridge, K. A., Lennon, B. W., Huddler, D. P., Matthews, R. G., and Ludwig, M. L. (2002) Domain alternation in B12-dependent methionine synthase: switching to the activation conformation. Nature Structural Biol. 9, 53-56.

Tani, T. H., Khodursky, A., Blumenthal, R. M., Brown, P. O., and Matthews, R. G. (2002) Adaptation to famine: a family of stationary phase genes revealed by microarray analysis. Proc. Natl. Acad. Sci., USA, submitted for

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