One-Way Street or Two-Way Traffic – How Enzymes adjust to the environmental conditions in the cell
More effective and safer medicines will be possible if we understand how the body detoxifies itself. The cytochrome P450 enzymes are the molecular machines responsible for the disposal by the human body of 80% of all medicines. These enzymes are also needed for the body to remove poisons and to manufacture many important molecules such as the sex hormones progesterone and testosterone. Understanding how the cytochromes P450 function is of great importance for human health.
New insight into how this family of enzymes functions has been provided by scientists at EML Research, in Heidelberg, Germany. Using computers to simulate how a mammalian cytochrome P450 interacts with chemicals such as progesterone, they now have an understanding of the ways into and out of the center of this protein. The functional part of the cytochromes P450 is buried in their centre, so understanding chemical access is critical to understanding the enzyme’s function. The new simulations show a channel that is different to those seen in the cytochromes P450 found in bacteria. However, the researchers propose that the mammalian enzyme may use the newly discovered channel and the channel seen in the bacterial enzymes, depending upon its cellular environment and the chemical compound that is entering it.
The scientists at EML Research propose two mechanisms in the newly investigated cytochrome P450: (1), a ‘one-way’ route whereby fat-soluble (lipophilic) substrates enter the enzyme from the membrane, and products leave the active site, via the newly discovered channel, directly into solvent; and (2) a ‘two-way’ route for access and egress of water-soluble compounds solely via the new channel. The proposed differences in the substrate access and product egress routes between the mammalian and bacterial cytochromes P450 highlights the adaptability of the P450 family to the requirements of different cellular locations and substrate specificity profiles.
The article (with videoclips from the simulations in the online-version) is published in: EMBO Reports, (2005) 6, 6, 584–589. doi:10.1038/sj.embor.7400420. Karin Schleinkofer, Sudarko, Peter J. Winn, Susanne K. Lüdemann, Rebecca C. Wade: Do mammalian cytochrome P450 show multiple ligand access pathways and ligand channeling?
The EML Research gGmbH (http://www.eml.research.de) is a non-profit institute conducting research in Information Technology and its applications. A strong focus is set on bioinformatics. Research is carried out in close collaboration with universities and other research institutes. EML Research projects are supported by the Klaus Tschira Foundation (KTS) (http://www.kts.villa-bosch.de), as well as by the European Union, the German Ministry of Research and Education (BMBF) and by the German Research Foundation (DFG). EML Research is a partner in the first German Center for Modeling and Simulation in the Biosciences (BIOMS, www.bioms.de). KTS and EML Research are housed in the Villa Bosch in Heidelberg, the former residence of Nobel Prize laureate Carl Bosch (1874 – 1940).
Rebecca Wade | alfa
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