Popular Science Presentation
Life is not possible without metals. Metal ions stabilize the structure of proteins and nucleic acids and catalyze chemical reactions that enzymes alone cannot accomplish. About half of all enzymes contain metal cofactors. Nature uses mainly the transition metals manganese, iron, cobalt, nickel, copper and zinc. These metals have different properties and fulfil different functions in the cell. Any imbalance in the cellular metal contents can lead to metals binding to the wrong enzymes, rendering these enzymes non-functional. Therefore, cells carefully balance metal uptake, storage and export so that their demands for each particular metal are exactly met. This process is called metal homeostasis. In bacteria, intracellular metal concentrations are regulated by specialized transcription factors. These proteins recognize and bind to specific metals and specific DNA sequences, thereby either blocking or enhancing the expression of neighbouring genes. Thus, when manganese is bound to a sensor responsible for regulating manganese uptake, the sensor blocks transcription of genes encoding for manganese importers, so that no more importers are being made when free manganese is already present in the cell.
For the cell to function properly, it is essential that each metal sensor responds specifically only to one metal ion. However, the transition metal ions used by Nature all look rather similar and can all bind to the same binding sites on proteins. How metal sensors can tell different metal ions apart and select the correct one is not completely understood, nor are the complex regulatory networks they control. We investigate the regulatory pathways controlling metal homeostasis in the bacterium Saccharopolyspora erythraea. This species is best known for being the producer of erythromycin, an important antibiotic. We study the metal sensors from S. erythraea using different biochemical, biophysical and molecular genetic methods in order to understand how they discriminate between different metal ions, and to find which genes they regulate under which conditions and how.
S. erythraea and related species from the actinomycete family produce a large variety of compounds such as erythromycin that are called secondary metabolites and are often potent antibiotics. However, most strains do not produce much or any of the metabolites they can make under laboratory conditions. Many interesting compounds therefore remain to be discovered. Since the cellular metal status has a profound influence on metabolism, this project may help the continuing efforts to improve secondary metabolite production in S. erythraea and other actinomycetes. On the other hand, many actinomycetes are human pathogens, such as Mycobacterium tuberculosis. Because our immune system fights invading pathogens by withholding essential metal ions from them, metal homeostasis is crucial for their survival. A better understanding of the regulatory networks controlling metal homeostasis can therefore also be harnessed in the fight against these pathogens.