Nonredox Nickel Enzymes

The importance of nickel enzymes, where nickel serves as an essential cofactor, in Archaea, bacteria, plants, and primitive eukaryotes, is well documented. Despite the fact that no enzyme utilizing Ni has been found in mammalian species, the impact of Ni biochemistry on human health is also significant. Indeed, nickel is known to cause cancer by an epigenetic mechanism, which appears to involve substitution of Ni(II) for Fe(II) in non- heme iron dioxygenases that are involved in DNA and histone demethylation. Furthermore, exposure to nickel compounds can also elicit an immune reaction: nickel contact dermatitis is one of the most common allergies in the modern world,5 and the molecular basis for the immune reaction is now beginning to emerge. Exposure to high levels of nickel has also been shown to impair the normal homeostasis of essential metal ions. Nonetheless, nickel is among the metals included in a group of “possibly essential elements” for animals and humans. Experiments using animal models have shown that nickel may be beneficial for bone composition and strength, for optimal reproduction, for energy metabolism, and for sensory function. The molecular basis for these functions is, however, not known. It is not surprising that human nickel deficiency has never been reported, probably because normal nickel intake greatly exceeds the estimated 25−35 μg/day metabolic requirement. In this Review, the current knowledge of the biochemistries, structures, and reaction mechanisms of enzymes whose active sites require nickel, and utilize it in a nonredox role, are discussed. In addition to excluding redox-active nickel sites (see the pertinent Reviews in this Thematic Issue), proteins isolated in proteomics facilities using nickel affinity columns that contain nickel, but whose native active site does not contain nickel, are also excluded. The focus is on the enzymes, and data from synthetic model systems is included only when it enhances knowledge of the reaction mechanism. The selection of nickel as a catalytic center for biological reactions is related to its flexible coordination geometry, which makes this metal a very versatile element for biological applications. To date, eight microbial nickel-containing enzymes have been well-characterized, including urease, hydrogenase, CO-dehydrogenase, acetyl-CoA synthase, methyl-CoM reductase, Ni-superoxide dismutase, acireductone dioxygenase, and glyoxalase I, while a few other possible nickel-dependent enzymes are emerging. The biological roles of nickel enzymes are conveniently divided into redox and nonredox roles. Unlike the more abundant biological redox metals iron and copper, aquated Ni(II) ions have no biologically relevant redox chemistry, as water will oxidize and reduce at potentials less extreme than those of the metal ion. Thus, the ligand environment is critical in adjusting the redox potential of Ni(II) into a biologically accessible range. In terms of nickel enzymes, this is usually achieved via coordination of anionic S-donors such as sulfide (as in carbon monoxide dehydrogenase) or, more commonly, thiolate sulfur in the form of cysteine ligands, which stabilizes the Ni(II/III) redox couple, or by coupling processes to sulfur redox chemistry (e.g., in methyl coenzyme M reductase). Thus, S-donor ligands are strongly associated with Ni redox enzymes, which include a novel superoxide dismutase, and several other enzymes including hydrogenase and CO- dehydrogenase/acetyl coenzyme A synthase that use Ni(II/III) redox chemistry to catalyze reactions that are involved in biological C1 chemistry. These enzymes have been extensively reviewed recently, and are covered by Reviews elsewhere in this Thematic Issue (see Valentine et al., Lubitz, and Ragsdale). In addition to adjusting redox potentials, the S-donor rich ligand environments often favor coordinatively unsaturated complexes with low-spin electronic structures. Nickel is also employed in enzymes as a Lewis acid catalyst, and in contrast to the redox enzymes, the coordination environments of these enzymes are composed exclusively of O/N-donor ligands. The coordination chemistry typically favors six-coordinate Ni(II) complexes that invariably have high-spin electronic structures. Three enzymes that utilize Ni(II) as a Lewis acid, urease, acireductone dehydrogenase, and glyoxalase I, are discussed here, with the goal of updating other comprehensive reviews through mid-2013.