Nickel in Biology

The practice of using nickel can be traced back through the history of civilization, with the metal incorporated into tools, weapons and currency. However, only relatively recently has nickel been added to the list of minerals employed as nutrients by living organisms. In the 1970s a specific physiological role for nickel was established when it was found to be a cofactor of the enzyme urease. This was a surprising find as urease had already earned a place in biochemical history 50 years earlier as the first enzyme to be crystallized, and the crystalline form of urease was used to prove that an ‘enzyme’ can be a pure protein. By the time nickel was found in urease, the idea that enzymes are proteins had become firmly ensconced, but it did raise the proposition that nickel was an essential trace element for the jack beans that supplied the urease protein for the study. This conclusion was quickly reinforced by evidence that nickel is required for the enzymatic activity of carbon monoxide dehydrogenase in the obligate anaerobe Clostridium pasteurianum.

Today, we have a substantial list of nickel enzymes, which covers a diverse array of chemical reactions and continues to grow. These enzymes are employed by many different organisms that inhabit all sorts of ecosystems around this planet, although a nickel enzyme has yet to be identified in animals. As with other transition metals, the chemical benefits of using nickel to catalyze biological reactions is accompanied by significant toxicity risks, so this element must be handled with care. Along these lines, our understanding of nickel biology is expanding beyond the enzyme metal centers to include cellular homeostasis mechanisms that are deployed by the organisms that use nickel, as well as how these systems adapt to the distinct environmental niches the organisms call home. This issue of Metallomics highlights recent work in some of these growing areas of nickel biology, illuminating fascinating details of these systems and raising new questions.

For example, some organisms have a huge appetite for nickel, whereas in others it is required in smaller amounts. In either case, ensuring an adequate supply of nickel is essential. Often there are multiple systems to guarantee import of this nutrient, but in many environments it is not clear what kind of nickel complexes are available to the organism and which make nickel accessible for uptake. So far, no small molecule chelator has been identified that is biosynthesized and excreted for the sole purpose of nickel selective uptake. Instead, there is now a case to be made that some bacteria take advantage of a reagent that they normally have in abundance, histidine, and its natural affinity for nickel, with tantalizing hints that other metabolites can be commandeered if needed.

Along these lines, the mini review by Chivers (DOI: 10.1039/C4MT00310A) surveys the recognition of nickel–histidine complexes by bacterial importers, and discusses how variations on this theme could provide selectivity for nickel complexes. This review also highlights outstanding questions about the nickel uptake process. Lebrette et al. (DOI: 10.1039/C4MT00295D) characterize and compare nickel binding to the solute-binding proteins of two membrane transporters from Staphylococcus aureus, suggesting different strategies of the recognition of nickel–histidine complexes. Furthermore, these studies suggest that nickel binding and uptake can be adjusted to a short supply of histidine by resorting to a complex containing an unusual thiazolidine-containing chelator. In a study about a very different type of nickel importer, Albareda et al. (DOI: 10.1039/C4MT00298A) performed a detailed analysis of the permease HupE from Rhizobium leguminosarum, and found that it is inhibited by histidine, which may reflect the chemical environment in the root nodule. When expressed in an orthogonal host, it was possible to pinpoint the source of energy for transport, leading to a conclusion of facilitated diffusion. At the other end of nickel homeostasis, Kim et al. (DOI: 10.1039/C4MT00318G) identify a nickel efflux pump and the accompanying metalloregulator in the soil bacteria Streptomyces coelicolor. A comparison of how this regulatory system responds to extracellular nickel versus that of nickel import reveals a surprisingly large window of nickel concentrations, spanning many orders of magnitude, in contrast to the tightly coordinated processes observed in other bacteria. This observation suggests that S. coelicolor are efficient at bringing in sufficient nickel and are tolerant to high levels of extracellular nickel, which could be an adaptation to the soil environment. In another example, Jones et al. (DOI: 10.1039/C4MT00210E) identify several new genetic targets of the Helicobacter pylori nickel responsive transcription factor HpNikR, dubbed a master regulator because of its expansive reach. Disruption of one of the new HpNikR gene targets, previously annotated as an iron transporter, can influence nickel accumulation, lengthening the list of nickel transporters in this bacteria and highlighting its commitment to nickel provision.

Once inside the cell, nickel ions are stored or distributed to their ultimate destination in enzyme active sites by accessory factors, some of which have naturally occurring histidine-rich sequences. This motif, which is so common in modern recombinant technology, presumably allows for reversible binding of multiple nickel ions. An example of such a protein is SlyD, implicated in the biosynthesis of [NiFe]-hydrogenase enzymes in E. coli. The activity of this protein is examined in detail by Pinske et al., (DOI: 10.1039/C4MT00019J) who tease out the role of SlyD in the production of the different hydrogenase isoenzymes expressed in E. coli during the stationary phase. Johnson et al. (DOI: 10.1039/C4MT00306C) investigate another accessory protein, HypA, which bridges the production of two nickel enzymes, hydrogenase and urease in Helicobacter pylori. This pathogen requires both nickel enzymes to survive in its preferred environment, the human stomach. Detailed analysis of HypA reveal structural aspects required for acid resistance and urease production in this organism.

Another key issue is how nickel proteins achieve selectivity for this metal above other biologically available metal ions. Given that mobile nickel is typically in the divalent oxidation state, it is reasonable to expect that the closest competitor is zinc. With both of these metal ions at the top of the Irving–Williams series, it is likely that selectivity strategies beyond thermodynamic binding preferences are necessary, and detailed structure/function analysis are revealing how nickel can provide a distinct allosteric impact on extended protein structure. For example, Suttisansanee et al. (DOI: 10.1039/C4MT00299G) compare the structures of two glyoxalase I enzymes from Pseudomonas aeruginosa, one that uses zinc as a cofactor and one that uses nickel. Features that confer metal selectivity were predicted and then confirmed by converting the zinc enzyme into a nickel-activated protein. Maillard et al. (DOI: 10.1039/C4MT00293H) explore the mechanism of nickel-selective activation of CnrX in Cupriavidus metallidurans, which triggers nickel efflux and is a key process in nickel resistance. Structure/function analysis of targeted mutations was performed to track down the connection between nickel binding and the ensuing allosteric response. Working with the same organism, Herzberg et al. (DOI: 10.1039/C4MT00297K) uncovered a link between nickel and zinc pathways when they investigated protein expression in bacteria growing under different conditions. Expression of nickel-containing hydrogenase, among other factors, is shut down in a mutant strain lacking key metal homeostasis factors but can be restored if zinc import is disrupted, raising the questions of how, and why, proper zinc allocation impacts production of the nickel enzyme. With regards to the [NiFe]-hydrogenase enzyme itself, Volbeda et al. (DOI: 10.1039/C4MT00309H) are zeroing in on the mechanistic detail of this fascinating system, by applying a combination of structural analysis and spectroscopy in the context of a wealth of spectroscopic and kinetic studies. This effort led to a model for one of the enzyme states along the reaction cycle, and uncovered a surprising transformation of the metal cluster in a mutant enzyme, suggesting how that mutant is more oxygen tolerant.

Finally, Tikhomirova et al. (DOI: 10.1039/C4MT00245H) explore some intriguing hints that the impact of nickel in biology extends beyond that of an enzyme cofactor. Disrupting nickel uptake in Haemophilus influenza highlighted a connection between intracellular nickel and stress responses as well as motility, suggesting that the availability of nickel may be a signal for switching between lifestyles for the bacteria. In another example of nickel biology, in this case when the metal is in the wrong place, Wezynfeld et al (DOI: 10.1039/C4MT00316K) discuss nickel toxicity in light of its ability to activate peptide bond cleavage. The examination of the hydrolysis of a particular target, alpha-1 antitrypsin, which is linked to several human diseases, revealed several specific products, and raised the question of whether long-term exposure to nickel could contribute to a deficiency of this protein.

Altogether, this collection highlights the richness of nickel biology, making one wonder, maybe Nature once said “If I only had a nickel…”.

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