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Press Release

Lauren Ward

For immediate release:
February 24, 2003

Carnegie Mellon University Chemistry Team Helps Reveal Key Structure, Fe(IV)=O Complex

PITTSBURGH—Using synthetic and spectroscopic tools, Carnegie Mellon University scientists and their colleagues at the University of Minnesota and Ewha Womans University, South Korea, have isolated and characterized a high-valent iron-oxygen complex that has been postulated to play a critical role in many different enzymes that catalyze a variety of biological reactions. Hypothesized for decades but never shown to exist until now, iron(IV)-oxo (Fe(IV)=O) species persist only fleetingly, and these elusive species have been the ongoing pursuit of chemists and biochemists alike.

The teams, headed by Carnegie Mellon Chemistry Professor Eckard Münck and University of Minnesota Chemistry Professor Lawrence Que, Jr., report their findings in the February 14 issue of Science. The paper is accompanied by a Science Perspective editorial. The work is also described in the News of the Week section of Chemical & Engineering News.

"Until recently the Fe(IV)=O species has been observed only in complexes containing the organic heme group. The present work describes the first crystal structure of a synthetic compound containing the Fe(IV)=O reactive unit," remarks Münck.

Fe(IV)=O is known to play an important role in enzymes containing heme groups, such as cytochrome P450, the major detoxifying enzyme in the liver. The Fe(IV)=O complexes are expected to be extremely "hot" in reacting with substrates; lifetimes as short as a trillionth of a second have been estimated for the putative Fe(IV)=O of cytochrome P450.

To capture the elusive Fe(IV)=O complex intermediate in a non-heme system, the researchers placed the reactive iron site in a bulky organic compound kept in a solvent at low temperature (-40 C). These procedures allowed otherwise short-lived intermediates to be trapped and characterized using powerful techniques such as Mössbauer spectroscopy (conducted at Carnegie Mellon) and x-ray crystallography (conducted at Minnesota). Through reiterations of these synthetic and analytic steps, the investigators perfected the preparation of complexes to a point where the Fe(IV)=O species was highly purified. In the case reported in Science, the lifetime of Fe(IV)=O was long enough to allow crystallization at -40C. The Carnegie Mellon team used the Mössbauer technique (at temperatures near absolute zero) to identify the oxidation state and quantify all the iron species, including Fe(IV)=O, with a precision approaching one percent.

"This is very exciting because the work demonstrates that the type of chemical environment supplied by a protein can stabilize Fe(IV)=O species. We are currently studying four enzymes suspected to use the Fe(IV) state. Our collaborators will be inspired by our result, and the race to get the first protein-bound Fe(IV)=O complex is on. I expect us to be involved in that discovery," Münck said.

A substantial number of critical reactive processes in biology involve dioxygen (O2), and the majority of these reactions involve enzymes that do not contain the heme group. These enzymes modify (activate) molecular oxygen into a form that reacts avidly in degradative and biosynthetic pathways with a variety of compounds, including fatty acids, steroids, DNA, L-dopa (a brain chemical used to treat Parkinson's disease), penicillin and methanol. For each individual system, detailed reaction schemes (catalytic cycles) have been proposed that describe the fate of the oxygen throughout the catalytic cycle. In such a cycle, electrons are rearranged and removed from the complex (oxidation) until an electron-deficient state (such as Fe(IV)=O) is attained. Fe(IV)=O, in turn, attacks other compounds to regain electrons (i.e., the other compounds become oxidized). Invariably, an Fe(IV)=O complex is postulated to be part of the cycle. Until now, however, no one has provided definite evidence for the existence of the species. With the present discovery, it is very likely that the postulated enzyme-bound species exists. An Fe(IV)=O species, containing a single oxygen atom bound to a highly oxidized iron atom, is an exceedingly potent oxidant and, compared to other oxidation states, the Fe(IV) state is exceedingly rare

During the past year Münck and graduate student Audria Stubna have studied seven novel Fe(IV)=O complexes with the Minnesota group. Using experimental and theoretical approaches, Stubna is deciphering the electronic structure of these novel systems. Ultimately, the solution of this problem will tell researchers why the enzymes can do what they do.

This research is funded by the National Institutes of Health, the Korea Science and Engineering Foundation, the Deutsche Forschungsgemeinschaft and the National Science Foundation.


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