Biochemistry of Metalloproteins
and Associated Diseases

Transition metals are the main constituents of the active sites of several enzymes and proteins where they provide redox, catalytic and structural properties. The most frequently used transition metals in biological systems are iron, manganese, copper, nickel, cobalt, molybdenum and zinc. Among them, iron is one of the most abundant. It is used in the form of heme iron centers, non-heme iron centers and iron-sulfur (Fe-S) clusters. The BMAD team is focusing its research on metallo-proteins, essentially Fe-S clusters: their biosynthesis, their roles in biology, the connections with iron and sulfur metabolisms and the diseases linked to the defects in the synthesis of these metallo-cofactors.
Fe-S clusters are small prosthetic groups of protein made of iron and sulfide ions. The most common forms in biological systems are the [2Fe2S] and [4Fe4S] clusters. Owing to their broad redox properties and their abilities to bind and react with small molecules and substrates, Fe-S cluster enzymes and proteins fulfill a wide range of biological functions: electron transfer for the production of ATP, redox and non-redox catalysis, signaling and maintenance of genome integrity. They are ubiquitous in living organisms (eukaryotes, bacteria and archaea), even some viruses use Fe-S clusters for their replication. Fe-S clusters are overly reactive and too labile to be obtained from food, they must be biosynthesized de novo in each cell by multi-protein machineries. Mitochondria is the primary site for the biosynthesis of [2Fe2S] clusters that are the building blocks for the assembly of [4Fe4S] clusters which occurs in both mitochondria and the cytosol. These processes are achieved in two main steps: assembly onto scaffold proteins and transfer/insertion into recipients enzymes. The mechanisms of these processes are complex and still unclear. Many diseases are caused by the defects in their biosynthesis or the dysfunction of a specific Fe-S enzyme, but the mechanisms leading to these diseases are still poorly understood. The lack of clear description of this fundamental process and the high medical importance of Fe-S clusters has spurred intensive research to understand how these cofactors are biosynthesized and assembled into proteins, which is one of the focus of the BMAD team.