Bioinorganic Chemistry of Nickel

Researchers have become increasing interested in the coordination chemistry of nickel complexes as models for the active sites in nickel containing enzymes^1-3. This is largely due to the discovery of nickel at the centers of many important enzymes^4-7. There are six nickel enzymes discovered so far, they are: urease⁸, NiFe hydrogenases, methyl coenzyme M reductase⁹, carbon monoxide dehydrogenase¹⁰, acetyl coenzyme A synthase¹¹ and more recently nickel superoxide dismutase (NiSOD)^{12, 13}. Additionally, there are several proteins required for the delivery and assembly of the nickel ions into the active sites of some of these proteins. For example, the nickel-uptake system in Escherichia coli consists of five proteins, NikABCDE. Recent spectroscopic studies of NikA suggest that the nickel site is six coordinate and comprised of five oxygen and/or nitrogen donors, and a single sulfur donor^14-16. There are additional E. coli enzymes in which nickel is important such as peptide deformylase and glyoxalase I which catalyze the deformylation of nascent polypeptides, and the isomerization reaction of the hemiacetal to the thioester of d-lactate formed from the reaction of pyruvaldehyde and glutathione respectively¹⁷. Since 1995, the structural biology of nickel proteins has greatly expanded largely due the X-ray structures of urease¹⁸, NiFe hydrogenase¹⁹, and methyl coenzyme M reductase²⁰. Many of the enzymatic reactions which occur in these centers are primarily due to the redox activity of the nickel atoms in the enzyme’s active site (Table (in pdf format)). In fact the proposed mechanisms of NiFe hydrogenase²¹, methyl-CoM reductase^22,23 and NiSOD^{12, 13} involves reduced (Ni^o,Ni⁺) and or oxidized (Ni³⁺) forms of nickel. In the case of Methyl-CoM reductase, and NiFe Hydrogenase a Ni(III)-Ni(II)-Ni(I) cycle has been proposed as part of the enzymatic cycle^24,25. It is important to note that in general, the nickel sites in the redox enzymes are dominated by cysteinate ligation whereas the nickel sites in nonredox, hydrolytic enzymes and transport proteins are dominated by O(N)-donor ligands. Therefore, the trend is for biological redox active nickel centers to be closely associated with sulfur-ligation whereas those with nonredox roles lack Ni-S bonds. It

is difficult to achieve this Ni(III)-Ni(II)-Ni(I) redox cycle in small molecule chemistry mainly due to the fact that the coordination environments which tend to stabilize Ni⁺ are much different from those that stabilize Ni^{3+ 26-28}. Nickel centers with reversible Ni(II)/Ni(I) and Ni(III)/Ni(II) couples and low Ni(III)/Ni(II) potentials are crucial to the activity of these nickel redox enzymes. The importance of these characteristics has lead to an increased interest in the synthesis of Ni(II) complexes with mixed N/S donors as structural, spectroscopic and redox models of the active sites of these redox enzymes^{29, 30}.

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Nickel Enzymes (active sites, reactions and biological distribution)
Enzyme	Ni-center	Reaction and Distribution
Urease		CO(NH2)2 à NH3 + CO2 + HNCO Bacteria and Plants
NiFe Hydrogenase*		2H^+(aq) + 2e^- ¾ H2 Bacteria
Methyl-CoM reductase*		Methanogenic Bacteria
CO dehydrogenase		CO + H2O à CO2 + 2H^++ 2e^- Photosynthetic Bacteria
Acetyl CoA synthase		CO2 + [CH3]-Co(III)balamin +SCoA +2e^- à CH3C(O)ScoA+ Co(I)balamin Methanogenic and Acetogenic Bacteria
Nickel Superoxide Dimutase*		2 O2^·- + 2H^+ à O2 + H2O2 Streptomyces