Abstract
Cadmium is a transition metal ion that is highly toxic in biological systems. Although relatively rare in the Earth’s crust, anthropogenic release of cadmium since industrialization has increased biogeochemical cycling and the abundance of the ion in the biosphere. Despite this, the molecular basis of its toxicity remains unclear. Here we combine metal-accumulation assays, high-resolution structural data and biochemical analyses to show that cadmium toxicity, in Streptococcus pneumoniae, occurs via perturbation of first row transition metal ion homeostasis. We show that cadmium uptake reduces the millimolar cellular accumulation of manganese and zinc, and thereby increases sensitivity to oxidative stress. Despite this, high cellular concentrations of cadmium (~17 mM) are tolerated, with negligible impact on growth or sensitivity to oxidative stress, when manganese and glutathione are abundant. Collectively, this work provides insight into the molecular basis of cadmium toxicity in prokaryotes, and the connection between cadmium accumulation and oxidative stress.
Highlights
Cadmium is a transition metal ion that is highly toxic in biological systems
We show that S. pneumoniae accumulates millimolar concentrations of transition metal ions, and that Cd2 þ dysregulates metal ion homeostasis by perturbing the Mn2 þ and Zn2 þ uptake and efflux pathways, via strikingly different mechanisms
To elucidate the hitherto unexplained molecular basis for Cd2 þ uptake via Mn2 þ transporters, we examined the interaction of Cd2 þ with the Mn2 þ -recruiting solute-binding protein (SBP) PsaA
Summary
Cadmium is a transition metal ion that is highly toxic in biological systems. relatively rare in the Earth’s crust, anthropogenic release of cadmium since industrialization has increased biogeochemical cycling and the abundance of the ion in the biosphere. It is conceivable that Cd2 þ may interact with the Psa permease, whether it causes injury to the cell by non-productively competing for metal ion uptake or by accumulation in the cytosol remains unclear. The increased sensitivity to oxidative stress associated with Cd2 þ toxicity is due to impaired Mn2 þ acquisition and not directly due to the intracellular accumulation of Cd2 þ ions, which are buffered on cellular glutathione. These findings highlight the challenge that biological systems encounter when non-physiological elements enter the biosphere. This study provides novel insights into the intracellular concentrations of transition metal ions in a Gram-positive cell, the mechanisms associated with their homeostasis, and how Cd2 þ dysregulates these processes
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