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. Bacteria usually have a number of metal sensors which are very similar to each other and recognize similar DNA sequences, yet each sensor reacts to a specific metal ion and regulates a specific set of genes. How metal sensors can tell different metal ions apart and select the correct one and how they recognize their DNA-binding sequences is not completely understood. We study the metal sensors from the bacterium Saccharopolyspora erythraea using different biochemical, biophysical and molecular biology methods in order to address these questions. Ultimately we aim to unravel the complex regulatory networks these metal sensors control.

Illustration of metal homeostasis in gram-positive bacteria such as S. erythraea, using the example of manganese. Different types of membrane importers pump manganese into the cell. When the intracellular manganese concentration reaches a certain level, manganese binds to the manganese-responsive repressor MntR and activates it, so that it can bind to the promoters of genes involved in manganese metabolism, such as those encoding manganese importers, and repress their transcription.

S. erythraea is best known for being the producer of erythromycin, an important antibiotic. 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.