Munich, Sep 06, 2021
Chlorophyll and heme are among the most important pigments in the world. Chlorophylls play essential roles in plant photosynthesis. Heme serves to transport oxygen in the bloodstream. The degradation products of these ‘pigments of life’, phyllobilins and bilins, respectively, have long been regarded solely as products of detoxification processes. Phyllobilins are products of the breakdown of chlorophyll and can be found in senescent leaves, in ripening fruits, and accumulate in vegetables during storage. Bilins are produced during the degradation of heme in the liver of mammals, and are found in lower vertebrates, algae and bacteria. In addition, theyare also the source of the bluish color of eggshells.
However, it is now clear that bilins also possess physiologically significant biological activities, serving, for instance, as potent antioxidants. “Recent work in my laboratory has shown that phyllobilins hold a large promise as bioactive compounds, too” says Simone Moser, who heads a research group in the Institute of Pharmaceutical Biology (Chair: Prof. Angelika Vollmar) in the Department of Pharmacy at LMU. “Our aim is to elucidate the physiological roles of phyllobilins, as they have been far less intensively studied than bilins.”
Identification of the proteins with which natural products interact is of fundamental importance for an understanding of their biological activities and physiological effects, as well as their mechanisms of action. However, little is known about the targets to which phyllobilins and bilins bind. Indeed, no target of phyllobilins has yet been identified in human cells, although we all ingest the phyllobilins found in plant based foods.
In a functional screen, Moser and her colleagues discovered that two colored phyllobilins – a yellow phylloxanthobilin and a pink phylloroseobilin – and the bilins bilirubin and biliverdin, all inhibit the migration of cancer cells in culture. The dynamics of the actin cytoskeleton, i.e. the polymerization and depolymerization of filaments made up of the protein actin, play a major role in the migration of cells. “In light of the importance of actin for the machinery that drives cell migration, we examined the effects of these four compounds on the morphology of the actincytoskeleton in cells, and investigated the dynamics of actin in vitro with the aid of fluorescently labeled actin,” explains Cornelia Karg, a doctoral student in Moser’s group and first author of the study, which appears in the journal Angewandte Chemie. “In cancer cells that had been exposed to phyllobilins, we observed an agglomeration of actin, and were able to show that both phyllobilins and bilins bind to a specific pocket in the protein. Binding inhibits actin nucleation and polymerization, with concomitant enhancement of filament depolymerization, and results in the destabilization of the actin cytoskeleton.
Nevertheless, the biological significance of these degradation products remains largely unknown. Many organisms – bacteria, plants and animals – produce natural substances that bind to actin, and several studies have indicated that these compounds might have a role to play in defending these organisms against pathogens. Interestingly, phyllobilins were recently associated with plant defense against pathogen attack.
With the identification of human actin as a binding partner for phyllobilins and bilins, we have taken one more step towards an understanding of the biological significance of the degradation products of two of the most important pigments in the biosphere, Moser concludes.
Publikation: Karg, C., Wang, S., Al Danaf, N., Pemberton, R., Bernard, D., Kretschmer, M., Schneider, S., Zisis, T., Vollmar, A., Lamb, D., Zahler, S. and Moser, S. (2021), Tetrapyrrolic pigments from heme- and chlorophyll breakdown are actin-targeting compounds. Angewandte Chemie International Edition. Accepted Author Manuscript. https://doi.org/10.1002/anie.202107813