Metallation and mismetallation of iron and manganese proteins in vitro and in vivo: the class I ribonucleotide reductases as a case study Original paper

What was studied?

The study focuses on the metallation and mismetallation of iron and manganese proteins, with specific attention to class I ribonucleotide reductases (RNRs). The research explores the challenges organisms face when inserting the correct metal into proteins that require them for biological function. These enzymes are important for deoxynucleotide production in both eukaryotes and prokaryotes. This study also investigates how iron and manganese are interchanged in metalloproteins, which has implications for the broader understanding of metal homeostasis and the environmental factors influencing the biological availability of these metals.

Who was studied?

The study doesn’t focus on individual organisms but rather on the biological systems and proteins involved in metallation, particularly class I ribonucleotide reductases (RNRs), which are found across various prokaryotes and eukaryotes. It delves into how these organisms use either iron or manganese for enzyme function, depending on environmental conditions and metal availability.

What were the most important findings?

The most significant finding of this study is that metallation, specifically of the class I RNRs, is determined more by the bioavailability of metals rather than a strict preference for one metal over the other. In particular, manganese can substitute for iron in many enzymes under certain conditions, such as oxidative stress, where metal homeostasis shifts to favor manganese. The research also emphasizes that, for some systems, mismetallation can occur without significant loss of activity, while for others, mismetallation renders the enzyme inactive. The class Ib RNRs, for instance, can use either a di-iron or a dimanganese cofactor to catalyze nucleotide reduction, with the manganese variant being especially important under conditions where iron is less available.

What are the greatest implications of this study?

This study sheds light on the adaptability of microbial systems to varying metal availability, which is crucial for understanding microbial physiology, especially under stress conditions. The ability to switch between iron and manganese cofactors could influence the design of antibiotics targeting pathogens that rely on manganese for RNR activity. Additionally, understanding the biochemical basis of mismetallation may lead to better insights into disease mechanisms, particularly in conditions where metal homeostasis is disrupted, such as neurodegenerative diseases or cancer.