Charles Williams, Ph.D.

Professor Emeritus, Biological Chemistry

Ofc: 4303 MSRB III
1150 W. Medical Center Drive
Ann Arbor, MI 48109-5606


(734) 647-6989

Areas of Interest

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, where flavin chemistry takes place, 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. It is thought that chemical differences between the third redox active group, a Cys-Lys-Gly-Gly-Gly-Cys in Plasmodium falciparum thioredoxin reductase and a Cys-Sec (selenoCys) in the human enzyme, will assist in drug design. Plasmodium falciparum is a causative agent of malaria, the fourth 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 their high requirements for reduced nucleotides.

My research is currently focused on a comparison of the mechanism and structure of thioredoxin reductase isolated from the human with that isolated from Plasmodium falciparum. In the totally in silico analysis of the two structures, it is evident that the two enzymes handle protons differently in the oxidative half-reaction. 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 NADPH to the flavin, from the reduced flavin to the so-called N-terminal redox active disulfide (the reductive half reaction), then to the C-terminal selenosulfide or disulfide and finally to thioredoxin (the oxidative half-reaction). 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. (Regrettably, I no longer take students.)

Honors & Awards

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

Published Articles or Reviews

Selected Publications

Reactivity of thioredoxin as a protein thiol-disulfide oxidoreductase.
Cheng Z, Zhang J, Ballou DP, Williams CH Jr.
Chem Rev. 2011; 111: 5768–83.

Investigations of the catalytic mechanism of thioredoxin glutathione reductase from Schistosoma mansoni.
Huang HH, Day L, Cass CL, Ballou DP, Williams CH Jr, Williams DL.
Biochemistry. 2011; 50: 5870–82.

Function of Glu-469' in the acid-base catalysis of thioredoxin reductase from Drosophila melanogaster.
Huang HH, Arscott LD, Ballou DP, Williams CH.
Biochemistry. 2008; 47: 12769–76.

Acid-base catalysis in the mechanism of thioredoxin reductase from Drosophila melanogaster.
Huang HH, Arscott LD, Ballou DP, Williams CH Jr.
Biochemistry. 2008; 47: 1721–31.

The relationship of the redox potentials of thioredoxin and thioredoxin reductase from Drosophila melanogaster to the enzymatic mechanism: reduced thioredoxin is the reductant of glutathione in Drosophila.
Cheng Z, Arscott LD, Ballou DP, Williams CH Jr.
Biochemistry. 2007; 46: 7875–85.

Identification of acid-base catalytic residues of high-Mr thioredoxin reductase from Plasmodium falciparum.
McMillan PJ, Arscott LD, Ballou DP, Becker K, Williams CH Jr, Müller S.
J Biol Chem. 2006; 281: 32967–77.

For a list of publications from PubMed, click HERE