For the first time, scientists from Dresden, Germamy,
proved that plant substances such as those found in red
wine, soy, or green tea can accelerate or retard vital processes in
cells.
These molecules bind to the protein actin which is implicated in cell
movement and cell division. According to experimental results
published recently in "Biophysical Journal" the ability of actin to
join to long chains is either hindered or improved. Surprisingly, it
has been shown that these substances also affect the rate at which
genetic information is processed in the cell's nucleus.
A large family of plant pigments, the flavonoids, comprises over 6000
structurally related substances found in fruit and vegetables of our
daily diet. They appear to evoke the positive health effects of green
tea or red wine. However, their functional mechanisms are diverse and
not well understood. This complicates the reliable assessment of their
beneficial effects as well as possible health risks. Many scientists
try to understand these mechanisms on a molecular level hoping to
learn from nature in order to design new compounds that can be used in
therapies of cancer or heart diseases.
Diagram of the steric structure of actin. The arrow
shows the probable position of the binding site for flavonoids.
The cutaway shows the predicted structure of the quercetin at the
binding site
Reference: PDB, ID 1j6z
The recent study reports two surprising
results that are related to the binding of flavonoids to the protein
actin. Actin is one of the best-studied and most abundant proteins.
Together with other biomolecules, it enables muscle contraction,
changing the cell shape, and separation of daughter cells during cell
division. Two years ago, biologists from the Technische Universit�t
Dresden were surprised to find that flavonoids can dock to actin in
the nucleus of living cells (Publication No. 1). Now, together with
the biophysics group at the Forschungszentrum Dresden-Rossendorf (FZD),
they proved in a test tube that flavonoids influence the growth of
chains of actin molecules, a process that is linked to the cellular
functions of actin (Publication No. 2).
Flavonoids can strengthen or weaken this process. Astonishingly, the
same dependency on flavonoids was observed for the speed at which the
genetic material is read from the DNA in the cell nucleus. These
results, according to Prof. Herwig O. Gutzeit from the TU Dresden, show that the direct biological effects of flavonoids on actin may
also influence the activity of genes in a cell.
The biophysicist Dr. Karim Fahmy from the Forschungszentrum
Dresden-Rossendorf (FZD) was able to demonstrate the molecular
mechanism by which flavonoids can affect actin functions. The
flavonoids function as switches that bind to actin and promote or
inhibit its functions. Using infrared spectroscopy, Fahmy studied the
interaction of actin with the activating flavonoid �epigallocatechin�
and the inhibitor �quercetin�. This method is well-suited for
demonstrating structural changes in large biomolecules without any
interventions that may affect the extremely sensitive proteins. Upon
addition of the selected flavonoids to actin, the structure of the
actin changes in a dramatic and typical way. Depending on the type of
flavonoid, the "actin switch" is set to increased or reduced
functional activity.
The mechanism appears obvious to the scientists: the effects of the
flavonoids are a function of their form. Actin itself is a flexible
molecule, which explains why various flavonoids can bind to actin in a
very similar way but nevertheless produce effects that range from
inhibition to stimulation. Flexible flavonoids match the structure of
the actin and create complexes that improve actin functions. More
rigid flavonoids force the actin into a structure that is less
compatible with its natural functions, thereby, inhibiting
actin-dependent cellular processes. Simulations of flavonoid binding
to actin performed in the bioinformatics group of Dr. Apostolakis at
the Ludwig-Maximilian University of Munich identified the putative
site where flavonoids interact with actin. The collaborative and
highly interdisciplinary efforts allowed to determine previously
unknown structure-specific functional mechanisms of flavonoids. This
knowledge facilitates the future search for compounds with improved
effectiveness and specificity that can be used to modulate actin
functions for therapeutic purposes.
Further Information and Source:
-
1) B�hl, M., C. Czupalla, S. V. Tokalov, B. Hoflack, and
H. O. Gutzeit. 2005:
Identification of actin as quercetin-binding protein: an approach
to identify target molecules for specific ligands
in:
Analytical Biochemistry, Volume 346, Issue 2, 15 November
2005, Pages 295-299; doi:
10.1016/j.ab.2005.08.037
-
2) Markus B�hl, Simon Tietze, Andrea Sokoll, Sineej Madathil, Frank Pfennig, Joannis Apostolakis, Karim Fahmy, and Herwig O. Gutzeit: Flavonoids Affect Actin Functions in Cytoplasm and Nucleus Biophysical Journal, 2007 Vol. 93: 2767-2780; Published ahead
of print on June 15, 2007 as doi:
10.1529/biophysj.107.107813
-
Forschungszentrum
Dresden-Rossendorf, FZD, Germany, is
a member of the Leibniz Association and is engaged in basic and
application-oriented research.