Microbial nickel: cellular uptake and delivery to enzyme centers

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ScienceDirect Microbial nickel: cellular uptake and delivery to enzyme centers Conor J Zeer-Wanklyn and Deborah B Zamble Nickel enzymes allow microorganisms to access chemistry that can be vital for survival and virulence. In this review we highlight recent work on several systems that import nickel ions and deliver them to the active sites of these enzymes. Small molecules, in particular L-His and derivatives, may chelate nickel ions before import at TonB-dependent outermembrane and ABC-type inner-membrane transporters. Inside the cell, nickel ions are used by maturation factors required to produce nickel enzymes such as [NiFe]hydrogenase, urease and lactate racemase. These accessory proteins often exhibit metal selectivity and frequently include an NTP-hydrolyzing metallochaperone protein. The research described provides a deeper understanding of the processes that allow microorganisms to access nickel ions from the environment and incorporate them into nickel proteins. Address Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada Corresponding author: Zamble, Deborah B ([email protected]. ca)

transporters that control uptake and efflux of nickel ions across cell membranes, intracellular nickel-binding proteins involved in metal ion distribution, and regulatory factors. These nickel systems present a fascinating display of the diverse bioinorganic chemistry available in biology. Furthermore, due to the fact that several nickel enzymes are virulence factors for human pathogens such as Helicobacter pylori and Escherichia coli [5,7,8], nickel enzymes and the support systems required for production are under consideration as possible antibiotic targets. In this review, we highlight recent insights into some of the nickel-binding factors that sustain nickel enzyme production in microbes (Figure 1). We begin with the metallophores and the import machinery that mediate nickel ion acquisition from the extracellular environment. This is followed by a discussion of the cytosolic proteins that collaborate to deliver the metal ions into the active sites of nickel enzymes. In particular, studies of the maturation of the nickel enzymes [NiFe]-hydrogenase, urease, and lactate racemase are described.

Current Opinion in Chemical Biology 2017, 37:80–88

Nickel metallophores

This review comes from a themed issue on Bioinorganic Chemistry

Recent work on nickel uptake indicates that in some cases the nickel import proteins recognize Ni(II) chelates instead of lone nickel ions. Small molecule ligands, either produced by the organism or supplied by the local environment, may help organisms access sufficient nickel in the face of competition for limited resources. After all, while the nickel requirement of some bacteria is substantial [9,10], environmental nickel is often scarce, typically at low nM concentrations [11,12].

Edited by Maarten Merkx and Antonio J Pierik

http://dx.doi.org/10.1016/j.cbpa.2017.01.014 1367-5931/ã 2017 Elsevier Ltd. All rights reserved.

Outer-membrane transporters

Introduction Nickel is a micronutrient used by a wide variety of organisms, which incorporate the metal ion into the catalytic centers of enzymes [1,2]. To date, nine nickel enzymes have been identified, and these systems play key roles in global nitrogen, carbon, and hydrogen cycles [1,3,4]. For instance, nickel enzymes catalyze the hydrolysis of urea in the case of urease, methane formation in the case of methyl CoM-reductase, and the reduction of protons to form hydrogen gas in the case of [NiFe]hydrogenase. The presence of nickel enzymes in an organism requires multiple auxiliary pathways that allow nickel ions to be used as essential cofactors while avoiding toxic side-effects [5,6]. Such systems include Current Opinion in Chemical Biology 2017, 37:80–88

The uptake of nickel complexes is consistent with the observation that several Gram-negative bacteria actively import nickel across the outer membrane via TonBdependent transporters (TBDTs). TonB, in cooperation with ExbB and ExbD, supplies energy to several dedicated transporters, which import molecules that cannot cross the membrane through diffusion or non-specific mechanisms [13]. Many metal-chelates require TBDT for import, including iron siderophores, heme, and cobalamin [13,14]. Nickel import through TBDTs has been observed in H. pylori [15,16], and is likely to occur in other species as well [14,17,18]. However, the structures of the nickel complexes transported have not been established. www.sciencedirect.com

Microbial nickel: cellular uptake and delivery to enzyme centers Zeer-Wanklyn and Zamble 81

Figure 1

TonB dependent transporter

Porin

Outer Membrane

CznC

TonB

FrpB4 CznB

ExbD ExbB

CeuE

Inner Membrane

FecD ABC-type

NixA

transporter

Secondary Importer

CznA

Efflux

FecE

[NiFe]Hydrogenase 2 H+ + 2 e– H2

SlyD HypA

NikR

Urease HypB Hy Hpn2

Urea + H2O

2 NH3+ CO2

Mature Enzymes

Hpn Ure(D/H)FG

Ni2+chaperones

UreE

Ni2+ storage

Gene regulation Current Opinion in Chemical Biology

Components of nickel metabolism in Helicobacter pylori. The schematic shows the paths of nickel ions as they are mobilized by H. pylori from outside the cell into the active sites of cytosolic nickel enzymes. This organism is used as an example that highlights many of the themes of microbial nickel homeostasis. It is possible that Ni(II) complexes enter the periplasm through TBDTs. Nickel can also reach the periplasm through low affinity porins in the outer membrane. The brackets surrounding the green spheres (nickel ions) indicate possible organic ligands such as histidine. Ni(II)(L-His)2 is a substrate for ABC-type nickel importers in many species, and may be a substrate of the CeuE, FecD/E system in H. pylori. Metallochaperone proteins deliberately guide nickel ions through the cytoplasm to the active sites of nickel enzymes such as urease and [NiFe]-hydrogenase. Hpn and Hpn2 contribute to nickel ion storage and urease maturation in this organism. Genetic regulation and nickel export (for instance by NikR and CznABC, respectively) are critical aspects of nickel homeostasis, however they are not discussed in this review.

Ni(II)(L-His)2 complex

After nickel ions reach the periplasm, they are subsequently transported across the inner-membrane in a process that often involves an ATP-binding cassette (ABC) transporter. These transporters include a periplasmic soluble binding protein (SBP) that captures the substrate and delivers it to the trans-membrane protein components. Recent structural studies of several nickel-binding SBPs suggested that L-His is a key piece of this process [19]. Histidine was initially implicated in E. coli nickel uptake because supplementation of the growth media www.sciencedirect.com

with L-His, but not D-His, enhanced nickel import, and the purified SBP NikA binds Ni(II)(L-His)2 [20]. A crystal structure revealed that NikA braces the Ni(II)(L-His)2 complex through electrostatic and p-stacking interactions, and that His-416 displaces a carboxylate ligand of one L-His to contact the nickel ion [21]. Perhaps as a result of these interactions, the arrangement of the ligands around Ni(II)(L-His)2 in NikA is distinct from Ni(II)(L-His)2 in solution (Figure 2). SBPs from other organisms have also been observed to bind Ni(II)-histidine complexes, with some variations in coordination Current Opinion in Chemical Biology 2017, 37:80–88

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[22,23,24]. It is possible that histidine coordination provides a mechanism of selective metal recognition. In competition experiments with other divalent metals in 100-fold excess over Ni(II), only Co(II) inhibited nickel uptake by E. coli [20]. This selectivity presumably arises because the SBPs can discriminate between the octahedral complexes formed by Ni(II) and Co(II) versus complexes of other metal ions [19].

Figure 2

O

(a)

O HN HN

N

OH

H Ni 2+ N N

O

N H NH

N

His 416 NikA-Ni(II)(L-His)2 O

(b)

O O

NH

O

Ni 2+

S

NH

N

N O

O Ni(II)(L-His) (2-methyl-2,4-thiazolidinedicarboxylate) (c)

O

H N

OH

L-His

NH 2

N CntK

O N

D-His

OH NH 2

HN

O Ado S

CntL

S NH 2 HO

OH NH 2

Ado

HO

O

N

N H

O

NH

Pyruvate + NADPH + H + CntM NADP + + H 2O

HO O

O

OH HO

N H

N H

O

NH N

Staphylopine Current Opinion in Chemical Biology

Nickel metallophores. Possible metallophores that are recognized by ABC-type nickel importers. (a) Ni(II)(L-His)2 is a substrate for the soluble binding protein component of several ABC-type nickel Current Opinion in Chemical Biology 2017, 37:80–88

It is unclear if the bacteria that can import nickel-histidine complexes are deliberately excreting L-His for the purpose of nickel recruitment, or simply taking advantage of a common extracellular molecule. For instance, microbes such as E. coli live in the mammalian digestive tract, which is rich in free histidine [25]. Furthermore, it is not known if the complexes form in the periplasm, or if they originate in the environment, and therefore oblige the activity of an outer-membrane transporter such the TBDTs described above. Finally, if a Ni(II)-chelate is imported, how is the nickel ion liberated from the complex? A recent study of the zinc starvation response in Acinetobacter baumannii suggested that catabolism of histidine is involved in mobilizing zinc from Zn(II)(L-His)2 [26], so it is possible that the analogous nickel complexes undergo similar processing. Other metallophores and metallophore-free systems

There is evidence that chelators besides histidine participate in nickel ion import. For example, Staphylococcus aureus NikA was found to bind a unique Ni(II) complex when it was incubated with the supernatant from a histidine-depleted S. aureus culture. This nickel complex was modeled as Ni(II)(L-His)(2-methyl-2,4-thiazolidinedicarboxylic acid) (Figure 2) [22]. The 2-methyl-2,4-thiazolidinedicarboxylic acid component can be produced from free cysteine in Salmonella typhimurium [27], and it is possible that similar activity is achieved in S. aureus. In another case, mass spectrometry revealed that the SBP CntA, also from S. aureus, bound a histidine-dependent nickel complex but not Ni(II)(L-His)2 [22]. It was noted that cntKLM, an operon upstream of cntABCDF, encoded proteins homologous to an epimerase and a nicotianamine synthase. This latter enzyme catalyzes the biosynthesis of metal chelators in a variety of organisms, but had not been described in bacteria. Subsequent analysis revealed that CntKLM assemble a metallophore, dubbed staphylopine, from D-His, the aminobutyric acid moiety of S-adenosyl methionine, pyruvate, and NADPH (Figure 2) [28]. Homologues of CntKLM are encoded in the genomes importers, including E. coli NikA. (b) Ni(II)(L-His)(2-methyl-2,4thiazolidinedicarboxylic acid) or a similar compound may bind NikA in S. aureus. (c) Staphylopine is biosynthesized by Staphylococcus aureus using D-His, the aminobutyric acid moiety of S-adenosyl methionine, pyruvate and NADPH. Staphylopine might serve as a nickel ion metallophore, however it is also involved in the import of other metals. www.sciencedirect.com

Microbial nickel: cellular uptake and delivery to enzyme centers Zeer-Wanklyn and Zamble 83

Figure 3

(a) Cys68

Cys65 2H+ + 2eS

Ni

S

2+

Fe S

S H2

N C C O C N

2+

Cys530

Cys533

KCX219

(b) His136 H N

O H2N + NH2 H2O

His248 NH

N HN

O

N

His138

2 NH3 + CO2

O

NH

N

NH

Ni2+

Ni2+ O

N

O H

O Asp362

His274 His200

(c) NH N

L-lactate

Ni2+

S O O–

Lys184

N H

O

HO P O

D-lactate

S

O

N

OH OH O

(d)

O AMP O P O O–

OH LarA

O N

LarC OH OH

CO2/HCO3– Ni2+ LarC

LarB AMP O O HO HO P O O–

O

O OH

O N

OH OH

2 ATP 2 LarE HS Cys

2 LarE Dha

O HS HO P O O–

O SH

O N OH OH

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84 Bioinorganic Chemistry

of other bacteria, such as Yersinia pestis and Pseudomonas aeruginosa, suggesting that staphylopine or similar metallophores may be used in a variety of species. Staphylopine appears to modulate the uptake of several different types of metal ions, so the selectivity of this import pathway for nickel remains to be established. Finally, there are also nickel-selective primary transporters that function without chelators. For instance, structural analysis of Thermoanaerobacter tengcongensis NikM, the SBP of an energy-coupling factor transporter, revealed Ni(II) bound to the N-terminal loop in a tetra-nitrogen square planar motif, which would not be favorable for other divalent metals [29].

Nickel metallochaperones in enzyme maturation Although nickel is an important nutrient in microbes, if uncontrolled it can modulate the activity of non-metalloenzymes, cause oxidative stress, or poison metalloenzymes by displacing the cognate metals [30,31]. One strategy to avoid these cytotoxic effects is the use of cytosolic metallochaperone proteins that deliberately guide nickel ions to the catalytic sites of nickel enzymes. Nickel metallochaperones may also play a role in preventing mismetallation by selectively delivering nickel ions while withholding other metals. Analysis of several nickel enzyme maturation systems has led to mechanistic insights, with a recent focus on the metallochaperones that are NTPases, a common component of these pathways. These NTPase components bind and hydrolyze the nucleotide triphosphate molecules ATP or GTP, and the nucleotide-loaded state can play a regulatory role by affecting other activities of the proteins such as protein-protein interactions and metal ion affinity.

[NiFe]-hydrogenase maturation

[NiFe]-hydrogenase enzymes reversibly catalyze the production of hydrogen gas from protons and electrons at a bimetallic active site (Figure 3) [32]. One of the final steps in [NiFe]-hydrogenase maturation is nickel insertion, which requires HypA, the GTPase HypB, and in some organisms SlyD (Figure 1) [32,33]. Each of these accessory proteins can independently bind nickel ions, but together they form multiprotein complexes that likely cooperate during nickel delivery [34]. Analysis of several HypB homologs revealed that the GTPase activity is influenced by an allosteric metal site

embedded in the GTPase domain [35,36,37], which binds nickel or zinc with distinct coordination [35,38]. In the case of the E. coli protein, in the GDP-loaded state HypB rapidly and specifically transfers nickel, but not zinc, to HypA [39]. This process is mediated by a combination of weakened nickel binding to HypB and a stronger HypB-HypA interaction, in comparison with GTPloaded HypB [40]. Furthermore, HypB disengages from the complex once HypA is loaded with nickel [40]. Thus, in this system GTP hydrolysis promotes unidirectional and selective transfer of nickel from HypB to HypA. HypA interacts directly with the hydrogenase precursor protein [34,41], suggesting that HypA subsequently delivers nickel into the enzyme active site. HypA and HypB are also present in archaea, but many features of the proteins are distinct. HypB from Thermococcus kodakarensis is an ATPase without any metal-binding capabilities [42], and ATP promotes complex formation with HypA [43]. Crystal structures of the T. kodakarensis proteins demonstrated that HypB induces conformational changes in HypA, resulting in the formation of a square-planar metal-binding site and increasing nickel ion affinity by two orders of magnitude [43]. These studies suggest that in this system the ATP-loaded state of HypB promotes the interaction with HypA and the activation of Ni(II) binding, which stimulates ATP hydrolysis and release of HypA to then deliver nickel to the hydrogenase enzyme.

Urease maturation

Urease, which catalyzes the hydrolysis of urea, contributes to nitrogen metabolism in many organisms and is a virulence factor in pathogens such as H. pylori, where it is involved in pH regulation [1,5]. The active site of urease includes two nickel ions bridged by a carbamylated lysine residue (Figure 3) [1,44], and assembly of this complex is typically accomplished by the Ure(D/H)EFG accessory proteins (Figure 1) [1,44]. In the current model UreDFG form a complex that docks with the urease enzyme through UreD to facilitate the insertion of nickel supplied by UreE [44–46]. In H. pylori, HypA and HypB contribute to the biosynthesis of urease as well as [NiFe]-hydrogenase [5]. HypA interacts with UreE to transfer nickel [47,48], so it is possible that HypA serves as a branch point that dictates whether nickel is funneled to [NiFe]-hydrogenase or the urease maturation systems. This part of the pathway may

(Figure 3 Legend) Nickel cofactors. (a) Desulfovibrio gigas [NiFe]-hydrogenase (PDB: 2FRV). [NiFe]-hydrogenase catalyzes the reversible reduction of protons to form molecular hydrogen, and does so at an elegant bimetallic centre. (b) Helicobacter pylori urease (PDB: 1E9Z). Urease catalyzes hydrolysis of urea at an active site that includes two nickel ions and carbamylated lysine (KCX). An (ab)3 heterotrimer is shown, however the urease heterotrimer assembles into an ((ab)3)4 dodecameric species that may be physiologically relevant. (c) Lactobacillus plantarum lactate racemase (PDB: 5HUQ). Lactate racemase enables the production D-lactate from L-lactate and utilizes a unique pincer-like nickel cofactor, the biosynthesis of which is shown in (d). The sulfurs for the thiocarboxylic acid groups of the final cofactor are obtained from cysteine residues of two LarE molecules, which are consequently converted into dehydroalanine (Dha). Current Opinion in Chemical Biology 2017, 37:80–88

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Microbial nickel: cellular uptake and delivery to enzyme centers Zeer-Wanklyn and Zamble 85

also serve as a metal selectivity filter, at least between nickel and zinc, given that zinc does not bind to the nickel site of HypA [39]. Furthermore, nickel binds preferentially to UreE with a different coordination than other metals [49,50], so the distinct impact of each metal on UreE structure could provide a means to ensure that only nickel is passed along the pathway to UreG. Analogous to HypB, UreG is a GTPase that binds metal, and there is a clear connection between metal binding and nucleotide hydrolysis. GTP loading of UreG favors association with UreE as well as nickel binding [51], so nickel is readily transferred from UreE to UreG in this state, before GTP hydrolysis results in nickel release from UreG [46,51]. The GTPase activity is accelerated by HCO3 and gated by UreF [45,46], suggesting that UreG is activated in the context of the Ure(D/H)FG-urease complex, and linking UreG activation to carbamylation of the urease active site. Recent structural, computational and mutagenesis work suggests the presence of a nickel channel in Ure(D/H)FG that connects UreG to a UreF metal-binding site and then passes through UreD/H to reach the active site of urease [52,53]. Lactate racemase maturation

Lactate racemization, an activity found in many Lactobacillus species, enables resistance to vancomycin because the produced D-lactate is incorporated into the cell wall peptidoglycan. Lactate racemase was recently designated a nickel enzyme, in part because activity in Lactobacillus plantarum was only detected when the enzyme-encoding operon larABCDE was co-expressed with larR(MN)QO, which is homologous to the nickel ABC-type importers described earlier, or when the growth media was supplemented with nickel [54]. Subsequent analysis revealed that the active site of lactate racemase, LarA, contains Ni(II) bound within a pincer-type complex that, while common in synthetic organometallic chemistry, has not been observed before in biology (Figure 3) [55]. The prosthetic group is covalently linked to a lysine of LarA, and it coordinates the nickel ion through carbon and two sulfurs, with a LarA histidine completing the square planar site [55]. The accessory proteins LarB and LarE build the organic framework of the cofactor from nicotinic acid adenine dinucleotide (Figure 3), and it is likely that the pincer receives nickel from the histidine-rich LarC before covalent attachment to LarA [56] (Figure 3). The LarBCE biosynthetic machinery is fairly widespread in prokarya, more so than the larA gene [54], suggesting that the pincer complex could be used in reactions beyond lactate racemization. Other maturation systems

Accessory proteins are also required for the maturation of the nickel enzymes carbon monoxide dehydrogenase (CODH), acetyl-CoA synthase (ACS), and methyl-coenzyme M reductase (MCR). In the first case, a nickelwww.sciencedirect.com

binding ATPase called CooC is required for nickel delivery to CODH [57]. In the second case, the product of the cooC2 gene, AcsF, does not bind nickel independently, but activates nickel delivery in an ATP-dependent process when it interacts with the ACS apoenzyme [58]. MCR harbors coenzyme F430, a nickel-containing tetrapyrrole, in the active site [3]. Recent work has revealed the F430 biosynthetic pathway, which includes a nickelspecific chelatase (CfbA) that inserts the nickel ion into the porphyrin ring [59].

Nickel storage

Some HypB and UreE homologues have histidine-rich regions and are known to contribute to nickel storage as well as enzyme maturation [6], but these histidine-rich sequences are not conserved in all organisms. Two additional proteins that contribute to nickel storage are Hpn and Hpn2 [5,6,60]. First identified in H. pylori [61,62], these are small histidine-rich proteins that can bind multiple nickel ions [63,64]. Furthermore, recent analysis suggested a more involved role for these proteins in delivering nickel to urease, possibly via direct interaction with the urease enzyme or with other accessory proteins [10]. Both proteins are required for H. pylori colonization of a mouse model, and phylogenetic analysis revealed that the genes are restricted to gastric strains of Helicobacter, suggesting that these factors were crucial for adaptation to the acidic environment of the stomach that is the niche of choice for these bacteria [10].

Conclusions Nickel enzymes are used by nature to catalyze vital reactions. This review focuses on recent efforts to understand some of the support systems that make possible the use of nickel as an enzyme cofactor. The processes discussed here, as well as regulation and nickel export, which are described separately in recent reviews [6,65,66], allow organisms to work with the dual nature of nickel as nutrient and toxin. However, as we expand our understanding of these fascinating systems, more questions arise. For instance, what are the mechanics of nickel translocation across the membrane? Does the cell need to mobilize nickel from metallophores, and if so, how and where? What is the fate of nickel proteins that bind non-cognate metals? Addressing these and other questions will advance our understanding of the rich world of nickel in biology. Note added in proof: A complete ABC nickel transporter was characterized in H. pylori [67]. This transporter, designated NiuBDE, is required for colonization of the mouse stomach and complements some of the activities of the other inner membrane transporter, the NixA permease. Current Opinion in Chemical Biology 2017, 37:80–88

86 Bioinorganic Chemistry

Acknowledgements The authors thank Michael D. Jones and Michael J. Lacasse for comments, and the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research for funding.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest

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Microbial nickel: cellular uptake and delivery to enzyme centers Zeer-Wanklyn and Zamble 87

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48. Yang X, Li H, Cheng T, Xia W, Lai Y-T, Sun H: Nickel translocation  between metallochaperones HypA and UreE in Helicobacter pylori. Metallomics 2014, 6:1731-1736. HypA forms a complex with UreE to facilitate nickel transfer, and this complex is weakened once UreE binds nickel. This work supports the idea that HypA can feed nickel into the urease maturation pathway, away from hydrogenase, and this activity may be particularly important in low nickel conditions.

34. Chan Chung KC, Zamble DB: Protein interactions and localization of the Escherichia coli accessory protein HypA during nickel insertion to [NiFe] hydrogenase. J Biol Chem 2011, 286:43081-43090. 35. Sydor AM, Lebrette H, Ariyakumaran R, Cavazza C, Zamble DB:  Relationship between Ni(II) and Zn(II) coordination and nucleotide binding by the Helicobacter pylori [NiFe]hydrogenase and urease maturation factor HypB. J Biol Chem 2014, 289:3828-3841. An investigation on the biochemical and structural impact of Ni2+ and Zn2+ on H. pylori HypB, including the first high resolution structure of a nickelloaded HypB. It reveals that metal discrimination is achieved by the metallochaperone, and describes mechanisms by which this could occur. 36. Cai F, Ngu TT, Kaluarachchi H, Zamble DB: Relationship between the GTPase, metal-binding, and dimerization activities of E. coli HypB. J Biol Inorg Chem 2011, 16:857-868. 37. Xia W, Li H, Yang X, Wong KB, Sun H: Metallo-GTPase HypB from Helicobacter pylori and its interaction with nickel chaperone protein HypA. J Biol Chem 2012, 287:6753-6763. 38. Gasper R, Scrima A, Wittinghofer A: Structural insights into HypB, a GTP-binding protein that regulates metal binding. J Biol Chem 2006, 281:27492-27502. 39. Douglas CD, Ngu TT, Kaluarachchi H, Zamble DB: Metal transfer within the Escherichia coli HypB-HypA complex of hydrogenase accessory proteins. Biochemistry 2013, 52:60306039. 40. Lacasse MJ, Douglas CD, Zamble DB: Mechanism of selective nickel transfer from HypB to HypA Escherichia coli [NiFe] hydrogenase accessory proteins. Biochemistry 2016, 55:68216831. In the GDP-loaded state, nickel binding to the GTPase domain of HypB is weaker but the complex with HypA is stronger, resulting in accelerated nickel transfer to HypA. Furthermore, HypA does not interact with HypB once it is loaded with nickel. These observations indicate that GTP hydrolysis by HypB modulates selective and directional nickel movement between the accessory proteins. 41. Sasaki D, Watanabe S, Kanai T, Atomi H, Imanaka T, Miki K: Characterization and in vitro interaction study of a [NiFe] hydrogenase large subunit from the hyperthermophilic archaeon Thermococcus kodakarensis KOD1. Biochem Biophys Res Commun 2012, 417:192-196. 42. Sasaki D, Watanabe S, Matsumi R, Shoji T, Yasukochi A, Tagashira K, Fukuda W, Kanai T, Atomi H, Imanaka T et al.: Identification and structure of a novel archaeal HypB for [NiFe] hydrogenase maturation. J Mol Biol 2013, 425:1627-1640. 43. Watanabe S, Kawashima T, Nishitani Y, Kanai T, Wada T, Inaba K,  Atomi H, Imanaka T, Miki K: Structural basis of a Ni acquisition cycle for [NiFe] hydrogenase by Ni-metallochaperone HypA and its enhancer. Proc Natl Acad Sci U.S.A. 2015, 112:77017706. The details of a HypA-HypB interaction from an archaeal species are uncovered. Protein complex formation is regulated by ATP/ADP cycling at HypB, and results in a high-affinity nickel-binding site on HypA. The www.sciencedirect.com

49. Higgins KA, Carr CE, Maroney MJ: Specific metal recognition in nickel trafficking. Biochemistry 2012, 51:7816-7832. 50. Zambelli B, Banaszak K, Merloni A, Kiliszek A, Rypniewski W, Ciurli S: Selectivity of Ni(II) and Zn(II) binding to Sporosarcina pasteurii UreE, a metallochaperone in the urease assembly: a calorimetric and crystallographic study. J Biol Inorg Chem 2013, 18:1005-1017. 51. Yang X, Li H, Lai T-P, Sun H: UreE-UreG complex facilitates  nickel transfer and preactivates GTPase of UreG in Helicobacter pylori. J Biol Chem 2015, 290:12474-12485. Urease maturation also relies on the GTPase UreG to regulate nickel delivery. The GTP/GDP state of UreG determines how it interacts with UreE, and if it will accept nickel. The authors also show that UreG can acquire nickel from HypA through UreE. 52. Zambelli B, Berardi A, Martin-Diaconescu V, Mazzei L, Musiani F,  Maroney MJ, Ciurli S: Nickel binding properties of Helicobacter pylori UreF, an accessory protein in the nickel-based activation of urease. J Biol Inorg Chem 2014, 19:319-334. Nickel chaperones are thought to play a role in guarding the cell from nickel toxicity, by sequestering it and delivering it specifically into nickel enzymes. In this paper the authors propose that in the case of urease, maturation factors cooperate to construct a nickel tunnel that would inject nickel directly into the urease active site. 53. Farrugia MA, Wang B, Feig M, Hausinger RP: Mutational and  computational evidence that a nickel-transfer tunnel in UreD Is used for activation of Klebsiella aerogenes urease. Biochemistry 2015, 54:6392-6401. UreD, a maturation protein that docks against the urease apo-enzyme, is shown to contain a nickel tunnel. This tunnel must be unobstructed for activation of urease, otherwise the enzyme is produced with less nickel bound and with higher levels of non-cognate metals such as zinc and iron. 54. Desguin B, Goffin P, Viaene E, Kleerebezem M, Martin Diaconescu V, Maroney MJ, Declercq JP, Soumillion P, Hols P: Lactate racemase is a nickel-dependent enzyme activated by a widespread maturation system. Nat Commun 2014, 5:3615. Identification of a new nickel enzyme. This investigation proves that nickel is an essential cofactor in LarA, the active lactate racemase. This discovery required that the authors recognize upstream factors as homologous to the ABC-type nickel transporters described in this review. 55. Desguin B, Zhang T, Soumillion P, Hols P, Hu J, Hausinger RP: A tethered niacin-derived pincer complex with a nickel-carbon bond in lactate racemase. Science 2015, 349:66-69. 56. Desguin B, Soumillion P, Hols P, Hausinger RP: Nickel-pincer  cofactor biosynthesis involves LarB-catalyzed pyridinium carboxylation and LarE-dependent sacrificial sulfur insertion. Proc Natl Acad Sci U S A 2016, 113:5598-5603. The authors propose a scheme for the biosynthesis of the LarA cofactor, which is a pincer-type complex different from anything seen before in Current Opinion in Chemical Biology 2017, 37:80–88

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bioinorganic chemistry. Making the cofactor is apparently an expensive process, including the sacrifice of two LarE proteins. Several specifics of cofactor assembly still need to be explored, and in particular the role of LarC in nickel delivery is poorly understood. 57. Jeoung JH, Giese T, Gru¨nwald M, Dobbek H: CooC1 from Carboxydothermus hydrogenoformans is a nickel-binding ATPase. Biochemistry 2009, 48:11505-11513. 58. Gregg CM, Goetzl S, Jeoung J-H, Dobbek H: AcsF catalyzes the  ATP-dependent insertion of Ni into the Ni, Ni-[4Fe4S] cluster of acetyl-CoA synthase. J Biol Chem 2016, 291:18129-18138. Nickel insertion into the nickel enzyme ACS requires ATP hydrolysis by AcsF. AcsF might therefore play a regulatory role analogous to the GTPases HypB and UreE in the maturation of this enzyme. 59. Zheng K, Ngo PD, Owens VL, Yang X-P, Mansoorabadi SO: The biosynthetic pathway of coenzyme F430 in methanogenic and methanotrophic archaea. Science 2016, 354:339-342. 60. Benoit SL, Miller EF, Maier RJ: Helicobacter pylori stores nickel to aid its host colonization. Infect Immun 2013, 81:580-584. 61. Gilbert JV, Ramakrishna J, Sunderman FW Jr, Wright A, Plaut AG: Protein Hpn: cloning and characterization of a histidine-rich metal-binding polypeptide in Helicobacter pylori and Helicobacter mustelae. Infect Immun 1995, 63:2682-2688.

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