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Charles H. Williams, Ph.D.

Professor Emeritus, Biological Chemistry
University of Michigan Medical School

B.S., University of Maryland
Ph.D., Duke University
Postdoctoral, University of Sheffield

Research Profile

The flavoenzyme thioredoxin reductase catalyzes the transfer of reducing equivalents from NADPH to thioredoxin, a 12 kDa protein containing a redox active disulfide. In its reduced form, thioredoxin activates transcription factors such as NF-kappa B in eukaryotes and OxyR in prokaryotes, acts as the donor of reducing equivalents in the conversion of nucleotides to deoxynucleotides, and works, in concert with the glutathione system, in maintaining the balance between thiols and disulfides in most cells, and, most important for our research, protects against reactive oxygen species. Thioredoxin reductase is found in two distinct types depending on the source, a 35 kDa form in prokaryotes, lower plants and fungi and a 55 kDa form in higher eukaryotes. Thioredoxin reductase is a member of the disulfide reductase family of flavoenzymes that includes lipoamide dehydrogenase and glutathione reductase. The 35 kDa form requires a large conformational change as part of catalysis to move reducing equivalents from the apolar interior of the enzyme to the surface where thioredoxin binds. In contrast, the 55 kDa form, which is similar to lipoamide dehydrogenase and glutathione reductase in mechanism and structure, has a third redox active group located near the C-terminus that shuttles reducing equivalents from the dithiol adjacent to the flavin to the protein substrate, thioredoxin. We propose that chemical differences between the third redox active group, a Cys-Cys in Plasmodium falciparum thioredoxin reductase and a Cys-Sec in the human enzyme, will assist in drug design. Plasmodium falciparum is a causative agent of malaria, the forth or fifth leading killer world-wide. Thioredoxin reductase is present in transformed cells at ten-fold the level found in normal cells, due to both the extreme sensitivity of these cells to reactive oxygen species and the their high requirements for reduced nucleotides. Malaria cells are also very sensitive to reactive oxygen species.

Research in my part of the Ballou laboratory is currently focused on the mechanism and structure of thioredoxin reductase isolated from human, Plasmodium falciparum and Drosophila melanogaster (a model for the Anopheles mosquito enzyme), and on thioredoxin glutathione reductase isolated from Schistosoma mansoni, the causative agent of another tropical disease, schistosomiasis. Enzymes in the disulfide reductase family catalyze electron transfer between a pyridine nucleotide and disulfide compounds. The flow of reducing equivalents in high Mr thioredoxin reductase is from NAPH to the flavin, from the reduced flavin to the so-called N-terminal redox active disulfide, then to the C-terminal disulfide and finally to thioredoxin. In catalysis, lipoamide dehydrogenase and glutathione reductase cycle between the oxidized and 2-electron reduced states while both types of thioredoxin reductase cycle between the 2-electron and 4-electron reduced states. Some of the intermediates in catalysis are readily distinguished spectrally, and we thus make extensive use of both conventional and rapid reaction spectrophotometry, and other techniques of physical biochemistry. This work would not be possible without extensive collaboration and this is the modus operandi of our laboratory; the references are indicative of this fact. Regrettably, I no longer take students.

Awards

1992 Distinguished Faculty Achievement Award
1993 Council's Choice Award for outstanding contributions made to the Inteflex Program
1995 Visiting Professor, Department of Biochemistry, Cambridge University, England
1978-2001 Research Career Scientist, U.S. Department of Veterans Affairs

Representative Publications

Arscott, L.D., Gromer, S., Becker, K., Schirmer, R.H., and Williams, C.H., Jr. (1997) The mechanism of thioredoxin reductase from human placenta is similar to the mechanisms of lipoamide dehydrogenase and glutathione reductase and distinct from the mechanism of thioredoxin reductase from Escherichia coli, Proc. Natl. Acad. Sci. USA 94, 3621-3626.

Williams, C.H., Jr., Arscott, L.D., Müller, S., Lennon, B.W., Ludwig, M.L., Wang, P-F., Veine, D.M., Becker, K. and Schirmer, R.H. (2000) Thioredoxin reductase: Two modes of catalysis have evolved. European J. Biochem. 267, 6110-6117. and Williams, C.H., Jr. an Introduction to the Minireview Series: Thioredoxin-thioredoxin reductase: A system that has come of age, p. 6101.

Bauer, H., Massey, V., Arscott, L.D., Schirmer, R.H., Ballou, D.P. and Williams, C.H., Jr. (2003) The Mechanism of high Mr thioredoxin reductase from Drosophila melanogaster. J. Biol. Chem. 278, 33020-33028, no. 35.PMID: 12816954

Gromer, S., Johansson, L., Bauer, H., Arscott, L.D., Rauch, S., Ballou, D.P., Williams, C.H.,Jr., Schirmer, R.H., Arner, E,S.J. (2003) Active Sites of Thioredoxin reductases: Challenging the importance of selenium. Proc. Natl. Acad. Sci. USA., 12618-12623.PMID: 14569031

Davioud-Charvet, E., McLeish, M.J., Veine, D.M., Giegel, D.A., Arscott, L.D., Andricopulo, A.D., Becker, K., Müller, S., Schirmer, R.H., Williams, C.H., Jr. and Kenyon, G., (2003) Mechanism-based inactivation of thioredoxin reductase from Plasmodium falciparum by Mannich bases: Implications for cytotoxicity. Biochemistry 42, 13319-13330. PMID: 14609342

Andricopulo, A.D., Akoachere, M.B., Krogh, R., Nickel, C., Mcleish, M.J., Kenyon, G.L., Arscott, L.D., Williams, C.H.,Jr., Davioud-Charvet, E., and Becker, K. (2006) Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents. Bioorg. Med. Chem. Lett. 16 (8) 2283-2292.PMID: 16458512

Johansson, L., Arscott, L.D., Ballou, D.P., Williams, C.H.,Jr. and Elias S. J. Arnér (2006) Characterisation of an active site mutant of the mammalian selenoprotein thioredoxin reductase that mimic the nonselenoprotein orthologue from Drosophila melanogaster. Free Radical Biology & Medicine 41, 649-656. PMID: 16863998

McMillan, P., Arscott, L.D., Becker, K., Ballou, D.P., Williams, C.H.,Jr., and Müller, S. (2006) Identification of acid-base catalysts of high Mr thioredoxin reductase from Plasmodium falciparum. J. Biol. Chem. 281, (44) 32967-32077.PMID: 16950793

Cheng, Z., Arscott, L.D., Ballou, D.P., Williams, C.H.,Jr. (2007) The relationship of the redox potentials of thioredoxin and of thioredoxin reductase from Drosophila melanogaster to the enzyme mechanism: Reduced thioredoxin is the reductant of glutathione in Drosophila. Biochemistry 46 (26) 7875-7885.PMID: 17550271

Haung, H-H., Arscott, L.D., Ballou, D.P., Williams, C.H.,Jr. (2008) Acid-base catalysis in the mechanism of thioredoxin reductase from Drosophila melanogaster. Biochemistry 47, 1721-1731.PMID: 18211101

Haung, H-H., Arscott, L.D., Ballou, D.P., Williams, C.H.,Jr. (2008) The Function of Glu-469' in the Acid-base catalysis in the mechanism of thioredoxin reductase from Drosophila melanogaster. Biochemistry 47, 12769-12776.PMID: 18991392

Huang HH, Day L, Cass CL, Ballou DP, Williams CH Jr, Williams DL. Investigations of the catalytic mechanism of thioredoxin glutathione reductase from Schistosoma mansoni. Biochemistry. 2011 Jul 5;50(26):5870-82. PMID: 21630672

Cheng Z, Zhang J, Ballou DP, Williams CH Jr. Reactivity of thioredoxin as a protein thiol-disulfide oxidoreductase. Chem Rev. 2011 Sep 14;111(9):5768-83. Epub 2011 Jul 27. PMID: 21793530 [PubMed - in process]

chaswill@umich.edu

Office: 4301B MSRB3, Box 5606
PH: (734)647-6989

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