Structure-Function Studies of Metal
Cluster Enzymes
Photosynthesis and the Environment
a. Water splitting enzyme. The mechanism of
water oxidation which is responsible for all of the dioxygen in
our atmosphere is being investigated at the atomic level using
spectroscopic methods: electron spin resonance spectroscopy to
examine the paramagnetic radicals produced during the
photochemical charge separation events, NMR spectroscopy to
identify the protein coordination environment surrounding the
catalytic sites.
b. Water oxidation catalysts. Synthesis of
functionally active catalysts for non-photosynthetic water
oxidation would greatly benefit the environment by enabling use
of dioxygen instead of air in many industrial processes and
combustions. There are no commercially available catalysts for
this process. Our approach is based on mimicking the structure of
the active site of the photosynthetic enzyme which splits water
into dioxygen and protons.
The human immunodeficiency virus type
1(HIV-1) is the etiologic agent of AIDS. Replication of the HIV-1
virus, and hence infection, requires DNA synthesis by a
retrovirus-encoded RNA-dependent DNA polymerase, or reverse
transcriptase (RT). HIV-1-RT is a multi-functional enzyme
required, not only, for the synthesis of the double-stranded
proviral DNA from the single-stranded retroviral RNA genome, but
also, cleavage of the retroviral RNA polymer in the form of a
hybrid DNA-RNA intermediate (ribonuclease H or RNAase H activity)
that allows transcription of the RNA fragments to proceed. We are
working with the pharmaceutical industry to characterize the pair
of metal ions that comprise the catalytic site of the RNAase
subdomain and several mutant proteins. A second project involves
the HIV-1 integrase, an enzyme responsible for integration of the
virus' DNA into the host's genome. One of the important goals is
to kill the AIDS virus by developing specific inhibitors of the
metal sites of these enzymes.
Nature has provided us with two different
classes of enzymes, called catalases, which protect us against
the destructive effects of hydrogen peroxide which forms during
normal cellular biochemistry to an appreciable extent. We study
the rare catalase produced by thermophillic bacteria. It has a
novel binuclear Mn center at its active site. We are working on
the mechanism of catalysis using magnetic resonance methods. This
research is aimed at developing both a fundamental understanding
of catalysis and a practical application to develop high
temperature enzymes for applications in bleaching. The insights
discovered from the enzyme studies are being used to synthesize
small molecule catalysts for selective oxidations.
The dimanganese enzyme,
arginase, is
responsible for metabolism of the amino acid L-arginine, a
product of protein metabolism. It may also be linked to formation
of the intracellular messenger nitric oxide. We are exploring the
mechanism of catalysis of this hydrolysis reaction using
biochemical and magnetic resonance techniques.
We have a research program in the synthesis
of metal complexes as functional models for the enzymes described
above. The oxidative class of these enzyme mimics are being
developed as potential catalysts for applications in
environmentally clean oxidations such as for chlorine-free
domestic laundry, paper/pulp bleaching and hydrocarbon
oxidations. As an example, we have recently synthesized the first
example of the [Mn4O4]6+ cubane to test as a potential model of
the photosynthetic water oxidation enzyme. The cubane core is
stabilized by coordination of six bidentate diphenylphosphinate
ligands between pairs of Mn ions across each of the six faces of
the cube.
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