Cytochromes P450 are key enzymes that are found in all aerobic systems and perform many vital functions, starting from detoxification of foreign compounds, through biosynthesis of hormones (e.g., sex hormones), all the way to brain chemistry and drug metabolism. All these features have made this enzyme a target for the drug industry, and for biomedical and chemical research, and have created an enormous interest in scientific methodologies that can provide details of the mechanism of action of these enzymes. This is precisely the insight covered in our paper in Chemical Reviews.

Top: Sason Shaik, Devesh Kumar, Samuël P. de Visser, Bottom: Ahmet Altun, Walter Thiel “The paper describes the action of a key enzyme in nature, P450, and elucidates the nature of its active species and its mechanisms of metabolism of a variety of molecules.”

To date this is the most complete and exhaustive theoretical treatment of the enzyme, its active species, its many reaction mechanisms, and the interplay between the active species and the protein environment. Most of these issues cannot be resolved by experimental means, and hence, our modeling has provided new and valuable insights, including new concepts, which address difficult experimental issues. These insights and concepts are well appreciated by the community of biochemists, bioinorganic chemists, enzymologists, and pharmacologists. As such, and in a way, this is a breakthrough paper in addressing biological problems from a chemical point of view. And this, along with the importance of the enzyme, may explain its rate of citation.

The paper describes an overview of structure and reactivity patterns of P450 enzyme, and hence contains a synthesis of knowledge about this key enzyme. In addition, the paper describes an effective methodology of investigating the active species of enzymes within their native protein environments.

But above all, the paper introduces two novel concepts: One is the concept of two-state reactivity (TSR) that has so far created order in the controversial reactivity data of the enzyme, and is therefore appreciated by the experimental community. The second is the concept of a "chameleon enzyme," which shows that the active species of the enzyme behaves like a chameleon and adapts its structure and electronic features to the environment that accommodates it.

As such, the properties of the active species is not intrinsic, but rather an emergent property of the interaction between the species and its protein environment. This last concept may have serious implications on the reactivity of the enzyme and the ability to direct the reactivity by use of external electric fields.

The paper describes the action of a key enzyme in nature, P450, and elucidates the nature of its active species and its mechanisms of metabolism of a variety of molecules. The work shows that the active species of the enzyme operates with two states that function as though there were two different species in the enzyme. It also shows that the active species behaves like a chameleon, changing its nature according to small changes in the protein environment.

In 1994, I was interested, together with the group of Professor Helmut Schwarz at the Technical University of Berlin, in the reactions of a small diatomic molecule, the iron-oxide cation, which exhibited very intriguing reactivity patterns. This was an interesting puzzle, and its solution made us aware that the notion of two-state reactivity may be wide-ranging and applicable to the P450 enzyme that possesses an iron-oxo group in its active species. This recognition led me to look at the enzyme, which has fascinated me ever since.

One of the major obstacles was the size of the enzyme, and, at the beginning, the calculations were difficult and cumbersome. We overcame these problems in 1998 by the use of simpler models, which eventually led us to develop the two concepts I have described above.

In 1999 I met Walter Thiel of the Max-Planck-Institut für Kohlenforschung, who suggested collaborating on this problem, using a theoretical method (called QM/MM) that allows treating the entire enzyme, and so we did and still continue to do. The insight gained from the simple model turned out to be an extremely good guide for the complex QM/MM calculations, which in turn validated the original ideas.

There are social implications in the sense that understanding the function of enzymes has always been an important quest among scientists.

Sason Shaik
Professor of Chemistry
The Institute of Chemistry and the Lise Meitner Minerva Center for Computational Quantum Chemistry
The Hebrew University
Jerusalem, Israel

Devesh Kumar
The Institute of Chemistry and the Lise Meitner Minerva Center for Computational Quantum Chemistry
The Hebrew University
Jerusalem, Israel

Samuël P. de Visser
Professor of Chemistry
School of Chemical Engineering and Analytical Science
The University of Manchester
Manchester, UK

Ahmet Altun
Max-Planck-Institut für Kohlenforschung
Mülheim an der Ruhr, Germany 

Walter Thiel
Professor of Chemistry
Max-Planck-Institut für Kohlenforschung
Mülheim an der Ruhr, Germany