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Professor, Inorganic Chemistry
B.S. with honors, 1966, University of Delaware
Ph.D. 1970, Northwestern University
Postdoctoral: 1970-1972, Purdue University
Email: cfshaw@ilstu.edu
Phone: (309)438-7207
Office: 311 Science Laboratory Building
Metal ions are
essential to the chemistry of life. DNA can not function as a
genetic material in the absence of counter ions to balance its
multiple negative charges; fully one-third of all proteins depend
on intimately associated metal ions to effect their biological
functions. Metal ions have profound effects on health and welfare
– some positive such as the therapeutic benefits of platinum
antitumor agents and gold antiarthritic agents and some negative
such as the environmental consequences of accumulated cadmium,
lead and mercury. The Shaw group applies a variety of experimental
and computational approaches to study the interaction of metal
ions with biological molecules and processes.
Gold compounds have a seventy year
history in the treatment of rheumatoid arthritis and are an
interesting model for the interaction of an exogenous metal with
living systems. Gold(I) administered in various drug formulations
is converted to aurocyanide and oxidized to gold(III) by the
immune system. We are presently using biomimetic conditions to
study the chemical basis for these transformations. Current work
focuses on auricyanide ([Au(CN)4-]) which
may carry oxidizing equivalents from the site of oxidation.
[Au(CN)4-] can be reduced by thiols such as
glutathione (GSH) to form aurocyanide ([Au(CN)2-]
and oxidized glutathione (GSSG). The reaction with glutathione
proceeds through two intermediates which are identifiable by
spectroscopic methods. Kinetic studies of other thiols and
isolation of the intermediates in which one or two thiolates
replace cyanides from gold are planned. A wide variety of
techniques will be applied to this problem. In addition,
computational studies using Gaussian 98 are underway to analyze
the preference of gold(III) for cis or trans arrangements of
square-planar dimethyl and dicyano gold(III) complexes, [Me2AuX2-]
& [Au(CN)2X2-].
Metallothionein (MT) is a
ubiquitous metal binding protein that consists of about 61 amino
acids, including 18 to 20 cysteines residues that form metal-thiolate
clusters with metal ions including Cd2+, Zn2+,
Cu+, Ag+, Au+, Bi3+
and Pt2+. As for many small proteins, its structure is
stabilized by the presence of metal ions and lost in their
absence. We are presently interested in testing a modification of
the folding pathway proposed by Stout and Robbins based on their
crystal structure of rabbit liver MT. They suggested a sequence
for binding of four Cd2+ ions to the 11 cysteine
residues of the αC domain. Their proposal ignores the
likely role of cysteine 50, which likely bridges between the first
two cadmium ions that bind to MT. 113 Cd NMR
spectroscopy, metal content analysis by ICP-AES, LC-MS and
UV-visible titrations will be used to examine the folding
mechanism using a synthetic 31-mer peptide which is a mutated to
contain only the cysteines likely to bind to the first two Cd2+
ions that associate with MT
The major histocompatibility
complex (MHC) molecules of the immune system determine our
reactions to a wide variety of infectious agents, yet in the case
of auto-immune diseases they react unfavorably with self-proteins.
They are large protein molecules consisting of two long chains
that associate with one another and then bind peptides of 15-20
amino acids from foreign and self substances. The I-Ad
MHC molecule is key to a reaction of mice against bovine (cow)
insulin, which is a model used to study gold-inhibition of the
immune system that may explain the action of gold against
rheumatoid arthritis. The structure of the I-Ad
molecule is known from x-ray crystallography, and it is of
interest to model the binding of Insulin A1-14, the key antigenic
determinant for reaction of mice to bovine insulin, with and
without the presence of gold bound to the insulin peptide. We have
developed an in silico model of A-Id and determined a
possible arrangement for the binding of Insulin A1-14 to it.
Calculations to compare the energy of the predicted conformation
and other possible conformations are needed.
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SELECTED PUBLICATIONS
J. Ejnik, J. Robinson, J. Zhu, H.
Fősterling, C. F. Shaw III, and D.H. Petering, “Folding Pathway of
Apo-Metallothionein Induced by Zn2+, Cd2+, or Co2+,
Journal of Inorganic Biochemistry, 88 (2002) 144-152.
M.J. Stillman, ed., and C. F. Shaw III and K. T. Suzuki, co-eds., "Metallothionein"
Journal of Inorganic Biochemistry,88 [Dedicated Issue,
No. 2] (2002) 119-139.
A.J. Canumalla, N. Al-Zamil, M. Phillips,
A.A. Isab, and C.F. Shaw III, "Redox and Ligand Exchange Reactions of
Potential Gold(I) and Gold(III) Cyanide Metabolites under Biomimetic
Conditions," Journal of Inorganic Biochemistry, 85 (2001) 67-76.
A. Muñoz, D.H. Petering, and C.F. Shaw III,
"Structure-Reactivity Relationships among Metallothionein Three-Metal
Domains: Role of Non-Cystein Amino Acid Residues in Lobster
Metallothionein and Human MT-3," Inorganic Chemistry, 39 (2000)
6115-6123.
A. Muñoz, F. Laib, D.H.
Petering, and C.F. Shaw III, "Characterization of the Cadmium Complex of
Peptide 49-61. A putative Nucleation Center for Cadmium-Induced Folding
in Rabbit Liver Metallothionein-IIA," Journal of Biological Inorganic
Chemistry, 4 (1999) 495-507.
A. Muñoz, D.H. Petering, and C.F. Shaw III, "Reactions of Electrophilic
Reagents that Target the Thiolate Groups of Metallothionein Clusters:
Preferential Reactions with the a-Domain," Inorganic Chemistry,
38 (1999).
C. F. Shaw III, Guest Editor, “Proceedings of the 4th
International Conference on Gold and Silver in Medicine”, Metal-Based Drugs, 6
[Special Issue, Nos. 4-5] (1999) 201-320.
C. F. Shaw III, "Gold-Based Medicinal
Agents" Chemical Reviews, 99 (1999) 2589-2600, [invited review].
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