Nickel-based Enzyme Systems

Abstract

Of the eight known nickel enzymes, all but glyoxylase I catalyze the use and/or production of gases central to the global carbon, nitrogen, and oxygen cycles. Nickel appears to have been selected for its plasticity in coordination and redox chemistry and is able to cycle through three redox states (1+, 2+, 3+) and to catalyze reactions spanning ∼1.5 V. This minireview focuses on the catalytic mechanisms of nickel enzymes, with an emphasis on the role(s) of the metal center. The metal centers vary from mononuclear to complex metal clusters and catalyze simple hydrolytic to multistep redox reactions. Of the eight known nickel enzymes, all but glyoxylase I catalyze the use and/or production of gases central to the global carbon, nitrogen, and oxygen cycles. Nickel appears to have been selected for its plasticity in coordination and redox chemistry and is able to cycle through three redox states (1+, 2+, 3+) and to catalyze reactions spanning ∼1.5 V. This minireview focuses on the catalytic mechanisms of nickel enzymes, with an emphasis on the role(s) of the metal center. The metal centers vary from mononuclear to complex metal clusters and catalyze simple hydrolytic to multistep redox reactions. Seven of the eight known nickel enzymes (Table 1) involve the use and/or production of gases (CO, CO2, methane, H2, ammonia, and O2) that play important roles in the global biological carbon, nitrogen, and oxygen cycles (1.Ragsdale S.W. J. Inorg. Biochem. 2007; 101: 1657-1666Crossref PubMed Scopus (125) Google Scholar). CODH 2The abbreviations used are: CODHCO dehydrogenaseACSacetyl-CoA synthaseARDacireductone dioxygenaseMCRmethyl-CoM reductaseSODsuperoxide dismutaseGlxglyoxylaseCFeSPcorrinoid iron-sulfur protein. interconverts CO and CO2; ACS utilizes CO; the nickel ARD produces CO; hydrogenase generates/utilizes hydrogen gas; MCR generates methane; urease produces ammonia; and SOD generates O2.TABLE 1Nickel-containing enzymesEnzymeReactionRef.Glx I (EC 4.4.1.5)Methylglyoxal → lactate + H2O (Reaction 1)7.Sukdeo N. Daub E. Honek J.F. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 445-472Crossref Scopus (7) Google ScholarARD (EC 1.13.11.54)1,2-Dihydroxy-3-oxo-5-(methylthio)pent-1-ene + O2 → HCOOH + methylthiopropionate + CO (Reaction 2)9.Pochapsky T.C. Ju T. Dang M. Beaulieu R. Pagani G.M. Ouyang B. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 473-500Crossref Scopus (27) Google Scholar, 10.Ju T. Goldsmith R.B. Chai S.C. Maroney M.J. Pochapsky S.S. Pochapsky T.C. J. Mol. Biol. 2006; 363: 823-834Crossref PubMed Scopus (51) Google ScholarNi-SOD (EC 1.15.1.1)2H+ + 2O2−̇ → H2O2 + O2 (Reaction 3)16.Bryngelson P.A. Maroney M.J. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 417-444Crossref Scopus (19) Google Scholar, 19.Barondeau D.P. Kassmann C.J. Bruns C.K. Tainer J.A. Getzoff E.D. Biochemistry. 2004; 43: 8038-8047Crossref PubMed Scopus (330) Google ScholarUrease (EC 3.5.1.5)H2N-CO-NH2 + 2H2O → 2NH3 + H2CO3 (Reaction 4)22.Ciurli S. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 241-278Crossref Scopus (30) Google Scholar, 23.Hausinger R.P. Karplus P.A. Wieghardt K. Huber R. Poulos T.L. Messerschmidt A. Handbook of Metalloproteins. John Wiley & Sons Ltd., West Sussex, United Kingdom2001: 867-879Google ScholarHydrogenase (EC 1.12.X.X)2H+ + 2e− ⇌ H2 (ΔE0′ = −414 mV) (Reaction 5)25.Lubitz W. Gastel M.V. Gärtner W. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 279-322Crossref Scopus (26) Google Scholar, 26.Vignais P.M. Billoud B. Chem. Rev. 2007; 107: 4206-4272Crossref PubMed Scopus (1222) Google ScholarMCR (EC 2.8.4.1)CH3-CoM + CoBSH → CH4 + CoM-SS-CoB (Reaction 6)42.Jaun B. Thauer R.K. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 323-356Crossref Scopus (47) Google Scholar, 43.Ragsdale S.W. Kadish K.M. Smith K.M. Guilard R. The Porphyrin Handbook. Academic Press, New York2003: 205-228Crossref Scopus (25) Google ScholarCODH (EC 1.2.99.2)2e− + 2H+ + CO2 ⇌ CO + H2O (E0′ = −558 mV) (Reaction 7)30.Lindahl P.A. Graham D.E. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 357-416Crossref Scopus (30) Google Scholar, 31.Ragsdale S.W. Pierce E. Biochim. Biophys. Acta. 2008; 1784: 1873-1898Crossref PubMed Scopus (780) Google ScholarACS (EC 2.3.1.169)CH3-CFeSP + CoASH + CO → CH3-CO-SCoA + CFeSP (Reaction 8)30.Lindahl P.A. Graham D.E. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 357-416Crossref Scopus (30) Google Scholar, 31.Ragsdale S.W. Pierce E. Biochim. Biophys. Acta. 2008; 1784: 1873-1898Crossref PubMed Scopus (780) Google Scholar Open table in a new tab CO dehydrogenase acetyl-CoA synthase acireductone dioxygenase methyl-CoM reductase superoxide dismutase glyoxylase corrinoid iron-sulfur protein. The nickel sites in enzymes exhibit extreme plasticity in nickel coordination and redox chemistry. The metal center in SOD must be able to redox processes with potentials that span from +890 to −160 mV (2.Miller A.F. Acc. Chem. Res. 2008; 41: 501-510Crossref PubMed Scopus (105) Google Scholar), whereas in MCR and CODH, it must be able to reach potentials as low as −600 mV (3.Holliger C. Pierik A.J. Reijerse E.J. Hagen W.R. J. Am. Chem. Soc. 1993; 115: 5651-5656Crossref Scopus (75) Google Scholar); thus, nickel centers in proteins perform redox chemistry over a potential range of ∼1.5 V! Because natural environments contain only trace amounts of soluble Ni2+, attaining sufficiently high intracellular nickel concentrations to meet the demand of the nickel enzymes requires a high affinity nickel uptake system(s) (4.Rodionov D.A. Hebbeln P. Gelfand M.S. Eitinger T. J. Bacteriol. 2006; 188: 317-327Crossref PubMed Scopus (230) Google Scholar), molecular and metallochaperones (5.Quiroz S. Kim J.K. Mulrooney S.B. Hausinger R.P. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 519-544Crossref Scopus (14) Google Scholar), and sensors and regulators of the levels of enzymes involved in nickel homeostasis (6.Phillips C.M. Schreiter E.R. Guo Y. Wang S.C. Zamble D.B. Drennan C.L. Biochemistry. 2008; 47: 1938-1946Crossref PubMed Scopus (48) Google Scholar). However, space limitations prevent coverage of these pre-catalytic events. GlxI and GlxII catalyze conversion of methylglyoxal, a toxic species that forms covalent adducts with DNA, to lactate (Table 1, Reaction 1) (7.Sukdeo N. Daub E. Honek J.F. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 445-472Crossref Scopus (7) Google Scholar). A single nickel ion in an octahedral coordination environment acts as a Lewis acid catalyst and remains in the 2+ state throughout the isomerization reaction (supplemental Fig. S1), which is consistent with the utilization of zinc at the GlxI active site in some organisms, including humans (8.He M.M. Clugston S.L. Honek J.F. Matthews B.W. Biochemistry. 2000; 39: 8719-8727Crossref PubMed Scopus (129) Google Scholar). The Ni2+ ion binds the hemithioacetal adduct between methylglyoxal and GSH, displacing a water ligand. General base catalysis by Glu122 leads to proton abstraction from the substrate, forming the coordinated enediolate intermediate. Reprotonation at C-2 promotes generation of the product S-d-lactoylglutathione, which undergoes hydrolysis to lactate and GSH in a separate reaction catalyzed by GlxII. ARD performs the penultimate step in the methionine salvage pathway (Table 1, Reaction 2) (9.Pochapsky T.C. Ju T. Dang M. Beaulieu R. Pagani G.M. Ouyang B. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 473-500Crossref Scopus (27) Google Scholar, 10.Ju T. Goldsmith R.B. Chai S.C. Maroney M.J. Pochapsky S.S. Pochapsky T.C. J. Mol. Biol. 2006; 363: 823-834Crossref PubMed Scopus (51) Google Scholar). ARD belongs to the cupin superfamily, and the structure reveals an octahedral high spin Ni(II) center, hexacoordinated by three histidines, one aspartic acid, and two waters (supplemental Fig. S2). Nickel neither undergoes redox changes nor binds O2; instead, the substrate acireductone (A, 1,2-dihydroxy-3-oxo-5-(methylthio)pent-1-ene) reacts directly with O2 to form the peroxo species (B), and nickel remains in the 2+ state throughout the reaction, like Cu1+ in the mechanism of copper amine oxidases (11.Samuels N.M. Klinman J.P. Biochemistry. 2005; 44: 14308-14317Crossref PubMed Scopus (26) Google Scholar). Nickel acts as a Lewis acid, promoting attack by the peroxo intermediate on the nickel-ligated carbonyl group to generate a cyclic intermediate (D) that decomposes to CO, formic acid, and a carboxylic acid. SOD emerged with the rise in O2 levels around 2 billion years ago (12.Zelko I.N. Mariani T.J. Folz R.J. Free Radic. Biol. Med. 2002; 33: 337-349Crossref PubMed Scopus (1634) Google Scholar) as part of a cellular defense system against reactive oxygen species generated by various reactions associated with oxygen metabolism, including respiration and oxidative stress events associated with macrophage and neutrophil infection (13.Somerville G.A. Banerjee R. Redox Biochemistry. John Wiley & Sons, Inc., Hoboken, NJ2008: 218-225Google Scholar, 14.Fridovich I. Banerjee R. Redox Biochemistry. John Wiley & Sons, Inc., Hoboken, NJ2008: 55-59Google Scholar). SOD targets superoxide (Table 1, Reaction 3), which directly destroys iron-sulfur clusters in redox enzymes, and reacts with nitric oxide to generate peroxynitrite, a powerful oxidant and nitrating agent (15.Fridovich I. Annu. Rev. Biochem. 1995; 64: 97-112Crossref PubMed Scopus (2755) Google Scholar). There are multiple SODs, the Cu/Zn-SODs, the Fe-SODs, the Mn-SODs, the cambialistic SODs (which can function with either manganese or iron), and the Ni-SODs, all of which catalyze the conversion of superoxide to O2 and H2O2 (Table 1, Reaction 3), with catalytic efficiencies (kcat/Km ∼ 109m−1 s−1) near the diffusion limit (14.Fridovich I. Banerjee R. Redox Biochemistry. John Wiley & Sons, Inc., Hoboken, NJ2008: 55-59Google Scholar, 16.Bryngelson P.A. Maroney M.J. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 417-444Crossref Scopus (19) Google Scholar). Originally isolated from Streptomyces seoulensis (17.Youn H.D. Kim E.J. Roe J.H. Hah Y.C. Kang S.O. Biochem. J. 1996; 318: 889-896Crossref PubMed Scopus (395) Google Scholar), the Ni-SOD gene (sodN) has been found in cyanobacteria, marine gammaproteobacteria, and a marine eukaryote (18.Dupont C.L. Neupane K. Shearer J. Palenik B. Environ. Microbiol. 2008; 10: 1831-1843Crossref PubMed Scopus (92) Google Scholar). Ni-SOD switches between a square planar N2S2 (Ni2+) and square pyramidal N3S2 (Ni3+) (supplemental Fig. S3) coordination environment (19.Barondeau D.P. Kassmann C.J. Bruns C.K. Tainer J.A. Getzoff E.D. Biochemistry. 2004; 43: 8038-8047Crossref PubMed Scopus (330) Google Scholar), composed of the sulfur atoms of two Cys residues and two peptide backbone nitrogens. Proteolytic processing of an inactive proprotein seeds the formation of the so-called nickel hook, a conserved 12-amino acid sequence that provides all of the essential interactions for metal binding (19.Barondeau D.P. Kassmann C.J. Bruns C.K. Tainer J.A. Getzoff E.D. Biochemistry. 2004; 43: 8038-8047Crossref PubMed Scopus (330) Google Scholar), and a catalytically active six-residue maquette has been synthesized (20.Schmidt M. Zahn S. Carella M. Ohlenschläger O. Görlach M. Kothe E. Weston J. ChemBioChem. 2008; 9: 2135-2146Crossref PubMed Scopus (36) Google Scholar). The Cys sulfur ligands appear to poise the Ni3+/2+ redox couple in the appropriate range for catalyzing both the reduction and oxidation of superoxide and to serve as a proton donor during catalysis (19.Barondeau D.P. Kassmann C.J. Bruns C.K. Tainer J.A. Getzoff E.D. Biochemistry. 2004; 43: 8038-8047Crossref PubMed Scopus (330) Google Scholar, 21.Szilagyi R.K. Bryngelson P.A. Maroney M.J. Hedman B. Hodgson K.O. Solomon E.I. J. Am. Chem. Soc. 2004; 126: 3018-3019Crossref PubMed Scopus (75) Google Scholar). The SOD reaction involves the binding of superoxide to the Ni2+ center, generating a Ni2+-peroxo species that undergoes proton and electron transfer to generate H2O2 and the oxidized Ni3+ center. Binding of a second superoxide generates a Ni3+-peroxo intermediate, which donates an electron back to the Ni3+ center to liberate dioxygen and re-form the starting Ni2+ state. Urease is key to the global nitrogen cycle because it catalyzes hydrolysis of urea, which is excreted by vertebrates, into ammonia and bicarbonate (Table 1, Reaction 4) (22.Ciurli S. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 241-278Crossref Scopus (30) Google Scholar, 23.Hausinger R.P. Karplus P.A. Wieghardt K. Huber R. Poulos T.L. Messerschmidt A. Handbook of Metalloproteins. John Wiley & Sons Ltd., West Sussex, United Kingdom2001: 867-879Google Scholar). Thus, urease is absent in vertebrates but facilitates nitrogen assimilation by plants, algae, and bacteria, a role that is underscored because urea is a major globally used soil fertilizer. Urease is also a virulence factor for pathogens in the animal gut and urinary tract, promoting host colonization by neutralizing the low pH in the stomach (24.Ernst F.D. Vliet M. S. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: Scopus Google Scholar). of urease and in the and of and are (22.Ciurli S. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 241-278Crossref Scopus (30) Google Scholar). Urease a center, with in a square pyramidal environment and in a (supplemental Fig. is to through a group and a from (22.Ciurli S. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 241-278Crossref Scopus (30) Google Scholar). in the 2+ the center acts as a Lewis acid a of urea with as high as and of the urea binds with its carbonyl oxygen to a in the urea the two nickel with one of the to and the group with and in the active of a proton to the group promotes attack of water on the urea carbonyl to formation of ammonia and which into bicarbonate and of two water ammonia and to re-form the catalytic center. catalyze the reduction of to H2 (Table 1, Reaction W. Gastel M.V. Gärtner W. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 279-322Crossref Scopus (26) Google Scholar, 26.Vignais P.M. Billoud B. Chem. Rev. 2007; 107: 4206-4272Crossref PubMed Scopus (1222) Google Scholar). H2 from the environment and couple its oxidation to the reduction of various electron CO2, and P.M. Billoud B. Chem. Rev. 2007; 107: 4206-4272Crossref PubMed Scopus (1222) Google Scholar). also contain cellular by to the are involved in H2 and P.M. Billoud B. Chem. Rev. 2007; 107: 4206-4272Crossref PubMed Scopus (1222) Google Scholar). Of the of one is a and complex P.M. Billoud B. Chem. Rev. 2007; 107: 4206-4272Crossref PubMed Scopus (1222) Google Scholar). contain at two and with the the active site 1) that is to a the which one to three clusters W. Gastel M.V. Gärtner W. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 279-322Crossref Scopus (26) Google Scholar). The of the center one CO and two which are to in its low spin state. There also a that the active including the but has catalytic and with a system to the of A. T. O. A. O. B. J. 2007; PubMed Scopus Google Scholar). mechanisms have been to the reaction P.M. Billoud B. Chem. Rev. 2007; 107: 4206-4272Crossref PubMed Scopus (1222) Google Scholar, S.O. Biochemistry. PubMed Scopus Google Scholar). H2 oxidation is (kcat/Km ∼ with a at Because the catalytic center is the of the H2 must through a in the to reach and with the active site Y. P. A. M.J. M. Biol. PubMed Scopus Google Scholar). The hydrogenase requires with H2 to generate the of an with a between the nickel and sites 1) W. Gastel M.V. Gärtner W. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 279-322Crossref Scopus (26) Google Scholar). appears to involve S.O. Biochemistry. PubMed Scopus Google Scholar). conversion of to a oxidation state by a transfer or electron transfer reaction, binding of H2 S.O. Biochemistry. PubMed Scopus Google Scholar). during the catalytic cycle is to by an oxidative mechanism that generate the intermediate, which undergoes two electron transfer to S.O. Biochemistry. PubMed Scopus Google Scholar). CODH catalyzes the oxidation of CO to CO2 (Table 1, Reaction to with CO or CO2 as and with CO as the only P.A. Graham D.E. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 357-416Crossref Scopus (30) Google Scholar, 31.Ragsdale S.W. Pierce E. Biochim. Biophys. Acta. 2008; 1784: 1873-1898Crossref PubMed Scopus (780) Google Scholar). The of CO oxidation to CO2 with the enzymes the of and of 2 109m−1 at low pH CO2 reduction can the of CO oxidation A. J. S.W. J. Am. Chem. Soc. 2007; PubMed Scopus Google Scholar). and of CO from to low CO can cycle CO as an intermediate in cycles and couple CO oxidation to H2 CO is to have been in the and the CODH and ACS reactions are to have been key to the of W. M.J. R. Soc. Biol. 2007; PubMed Scopus Google Scholar). There a nickel CODH, and nickel and a and P.A. Graham D.E. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 357-416Crossref Scopus (30) Google Scholar, 31.Ragsdale S.W. Pierce E. Biochim. Biophys. Acta. 2008; 1784: 1873-1898Crossref PubMed Scopus (780) Google Scholar). The nickel CODH is a metal clusters and two and one The catalytic (supplemental Fig. is a to a and is the The and are clusters that as a to transfer between the and redox like of the mechanism S.W. 2008; PubMed Scopus Google Scholar) involves CO binding to nickel and water to in the of the by of the water to generate an active the group the complex to form a complex that by to the nickel and atoms S.W. M. M. W. O. V. J. Biol. Chem. 2007; PubMed Scopus Google Scholar). which the of reaction, CO2 is generated and as two are to the involves electron transfer from the to the and in the redox and in the are from CODH to or electron ACS with CODH to form a that and (Table 1) to catalyze acetyl-CoA from CO2, a group by the and reaction, CO is as an intermediate that is a between the CODH and ACS active sites J. S.W. Drennan C.L. Biochemistry. 2008; 47: PubMed Scopus Google Scholar). The active site of ACS is the a that is to the nickel which in is to (supplemental Fig. The coordination environment of the active site of and the is to that of the in which a is to a site Y. Biochem. 2000; PubMed Scopus Google Scholar). of the ACS reaction have been (1.Ragsdale S.W. J. Inorg. Biochem. 2007; 101: 1657-1666Crossref PubMed Scopus (125) Google Scholar, P.A. Graham D.E. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. 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PubMed Scopus Google Scholar). only is the in and only the form of the can catalytic mechanisms are and the for mechanism has been B. Thauer R.K. Sigel A. Sigel H. Sigel R.K.O. Nickel and Its Surprising Impact in Nature. John Wiley & Sons Ltd., West Sussex, United Kingdom2007: 323-356Crossref Scopus (47) Google Scholar, 43.Ragsdale S.W. Kadish K.M. Smith K.M. Guilard R. The Porphyrin Handbook. Academic Press, New York2003: 205-228Crossref Scopus (25) Google Scholar). I involves a intermediate, and a of performs a attack on methyl-CoM to form a intermediate and to electron transfer from to the generates and a in the reacts with CoBSH to form a as proton transfer from to the group generates Ni(II) and in the the CoM-SS-CoB and active to reacts with at which promotes of the generating a with the sulfur of forming a the a hydrogen from CoBSH to form and a on involves formation of Ni(II) and the and as the active state and the the major role of nickel is to by a redox and to the product of by forming a coordination complex with the sulfur of has been catalysis the of the nickel T.C. B. J. Am. Chem. Soc. PubMed Scopus Google Scholar) because the nickel center is to and and of catalytic in some of the eight enzymes some the in nickel the and new nickel of nickel in that nickel is an essential for E. K. Rev. 2002; PubMed Scopus Google Scholar) and nickel is at in the The of John Wiley & Sons, Inc., New Scholar), neither the of the nickel nor a single has been I to to the and have on nickel enzymes in and to H. and on with