Marc Solioz

In recent years, the “Copper-2 Hypothesis” has been put forth in an attempt to explain the epidemic of Alzheimer’s disease (AD) in the Western world. According to this hypothesis, “free” copper (copper-2) in drinking water, dietary supplements, and meat is the chief cause of the increased incidence of AD in recent decades. In contrast to the US, copper plumbing for drinking water is not used in Switzerland and tap water is very low in copper. Other “risk” factors including dietary supplements and meat consumption are also lower in Switzerland than in the US. Yet, the incidence of AD is closely similar in the two countries. This contradicts the Copper-2 Hypothesis. Impact statement: The Western world is faced with an Alzheimer’s epidemic. Identifying the life style and anthropogenic factors involved has become a priority. This is a formidable challenge due to the complexity and the slow progression of the disease. A hypothesis put forth by George Brewer postulates divalent copper (copper-2), chiefly present in drinking water from copper pipes, to be a major risk factor for Alzheimer’s disease. In Switzerland, copper pipes are not used for drinking water, but the frequency of Alzheimer’s disease is similar to that of other Western countries. This contradicts Brewer’s hypothesis and suggests that other factors are responsible for today’s Alzheimer’s epidemic.

Xenon is frequently used as a general anesthetic in humans, but the mechanism remains an issue of debate. While for some membrane proteins, a direct interaction of xenon with the protein has been shown to be the inhibitory mechanism, other membrane protein functions could be affected by changes of membrane properties due to partitioning of the gas into the lipid bilayer. Here, the effect of xenon on a mechanosensitive ion channel and a copper ion-translocating ATPase was compared under different conditions. Xenon inhibited spontaneous gating of the Escherichia coli mechano-sensitive mutant channel MscL-G22E, as shown by patch-clamp recording techniques. Under high hydrostatic pressure, MscL-inhibition was reversed. Similarly, the activity of the Enterococcus hirae CopB copper ATPase, reconstituted into proteoliposomes, was inhibited by xenon. However, the CopB ATPase activity was also inhibited by xenon when CopB was in a solubilized state. These findings suggest that xenon acts by directly interacting with these proteins, rather than via indirect effects by altering membrane properties. Also, inhibition of copper transport may be a novel effect of xenon that contributes to anesthesia.

Desulfovibrio sp. A2 is a novel Gram-negative sulfate-reducing bacterium that was isolated from sediments of the Norilsk mining/smelting area in Russia. The organism possesses a monocistronic operon encoding a 71 kDa periplasmic multicopperoxidase, which we call DA2_CueO. Histidine-tagged DA2_CueO expressed from a plasmid in Escherichia coli and purified by Ni–NTA affinity chromatography oxidizes Cu+ and Fe2+, and exhibits phenol oxidase activity with 2,2-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid), 2,3-dihydroxybenzoic acid and 2,6-dimethoxyphenol as substrates, using O2 as the oxidant. When expressed in an E. coli cueO knock-out strain, DA2_CueO exhibits phenol oxidase activity in vivo and enhances the copper tolerance of the strain. These findings indicate that the DA2_CueO gene of Desulfovibrio sp. A2 encodes a multicopperoxidase with a role in metal ion resistance. The enzyme displays some novel structural features, which are discussed.

The killing of bacteria on metallic copper surfaces in minutes to hours is referred to as contact killing. Why copper possesses such strong antimicrobial activity has remained enigmatic. Based on the physicochemical properties of metals, it was recently predicted that cadmium should also be active in contact killing [Hans et al., Biointerphases 11, 018902 (2010)]. Here, the authors show that cadmium is indeed antimicrobial. It kills three logs of bacteria in 9 h, compared to copper which kills eight logs of bacteria. Metallic silver kills less than one log of bacteria in 9 h. These findings support the novel concept whereby oxide formation, metal ion dissolution, and a Pearson soft character are the key factors for a metal to be antibacterial. Based on these parameters, copper and cadmium are expected to be the two most antibacterial metals.

The active transport of ions across biological membranes requires their hydration shell to interact with the interior of membrane proteins. However, the influence of the external lipid phase on internal dielectric dynamics is hard to access by experiment. Using the octahelical transmembrane architecture of the copper‐transporting P_1B‐type ATPase from Legionella pneumophila as a model structure, we have established the site‐specific labeling of internal cysteines with a polarity‐sensitive fluorophore. This enabled dipolar relaxation studies in a solubilized form of the protein and in its lipid‐embedded state in nanodiscs. Time‐dependent fluorescence shifts revealed the site‐specific hydration and dipole mobility around the conserved ion‐binding motif. The spatial distribution of both features is shaped significantly and independently of each other by membrane lateral pressure.