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?
Scientific Contact:
Dr. Rebecca Wade
Group Leader
Molecular and Cellular Modeling Group (MCM)
EML Research gGmbH
phone: +49-6221-533-247
fax: +49-6221-533-298
[email protected]
