Flavonoids Govern Cell Processes, Enhance Health

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.

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 Universität Dresden were surprised to find that flavonoids can dock to actin in the nucleus of living cells_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 actin₂. 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.

Articles:

1. Böhl, 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: Anal. Biochem. 346:295-9.

2. Böhl, M., Tietze, S., Sokoll§, A., Madathil+, S., Pfennig, F., Apostolakis, J., Fahmy, K., Gutzeit, H.O.: "Flavonoids affect actin functions in cytoplasm and nucleus“, in: Biophysical Journal, Vol. 93, Nr. 8 (2007).