Structure, function, and biosynthesis of nickel-dependent enzymes

Abstract

Nickel enzymes, present in archaea, bacteria, plants, and primitive eukaryotes are divided into redox and nonredox enzymes and play key functions in diverse metabolic processes, such as energy metabolism and virulence. They catalyze various reactions by using active sites of diverse complexities, such as mononuclear nickel in Ni-superoxide dismutase, glyoxylase I and acireductone dioxygenase, dinuclear nickel in urease, heteronuclear metalloclusters in [NiFe]-carbon monoxide dehydrogenase, acetyl-CoA decarbonylase/synthase and [NiFe]-hydrogenase, and even more complex cofactors in methyl-CoM reductase and lactate racemase. The presence of metalloenzymes in a cell necessitates a tight regulation of metal homeostasis, in order to maintain the appropriate intracellular concentration of nickel while avoiding its toxicity. As well, the biosynthesis and insertion of nickel active sites often require specific and elaborated maturation pathways, allowing the correct metal to be delivered and incorporated into the target enzyme. In this review, the phylogenetic distribution of nickel enzymes will be briefly described. Their tridimensional structures as well as the complexity of their active sites will be discussed. In view of the latest findings on these enzymes, a special focus will be put on the biosynthesis of their active sites and nickel activation of apo-enzymes.

Keywords: enzyme maturation; metallocluster; metalloenzymes; nickel active site; redox enzymes.

Figure 1

Schematic amino acid sequences and metal‐binding motifs of Ni‐enzymes. Residues involved in Ni or Fe binding are highlighted in green and orange, respectively. Residues involved in both Ni and Fe binding are highlighted in magenta. Residues in interaction with cofactors are highlighted in blue. Accession number in UniProtKB is in italics. Residues constituting the active site are annotated. RrCODH: monomer of CODH from R. rubrum; MtACS: α susbunit of CODH/ACS from Moorella thermoacetica; DgH₂ase: small (HydA) and large (HydB) subunit of [NiFe]‐H₂ase from Desulfovibrio gigas, sequence signal of HydA (1–23) for periplasmic translocation and propeptide (537–551) processed in HydA during maturation are in barred; MmMCR: α (McrA), ß (McrB), and ɤ (McrG) subunits of MCR from Methanothermobacter marbugensis; SsNi‐SOD: monomer of Ni‐SOD from Streptomyces seoulensis, the processed propeptide (1–14) is in barred; SpUrease: α, ß, and ɤ subunits of urease from Sporosarcina pasteurii; LpLarA: LarA from Lactobacillus planetarium; EcGlxI: monomer of Glx I from E. coli; KoARD: Ni‐ARD from Klebsellia oxytoca

Figure 2

Overall structures of Ni‐enzymes. (a). CODH dimer from Rhodospirillum rubrum (PDB code: 1JQK). The N‐terminal domain is in magenta and the two Rossman‐like domains are in green and blue. C‐clusters are depicted in spheres B. α₂ß₂ tetramer of CODH/ACS from Moorella thermoacetica (PDB code: 1OAO). The two ß subunits of CODH are colored in blue and cyan. The two ACS subunits are in open or closed conformation. A‐ and C‐clusters are depicted in spheres. C. Archetypical structure of [NiFe]‐hydrogenase from Desulfovibrio gigas (PDB code: 1FRV). The large subunit is in magenta and the small subunit in green. The buried active site is depicted in spheres. D. Dimer of αßɤ MCR from Methanothermobacter marbugensis (PDB code: 3POT). The α, ß, and ɤ subunits are in blue, cyan, and magenta, respectively. Coenzyme F430 is depicted in orange and Coenzyme B in green. E. Ni‐SOD hexamer from Streptomyces seoulensis (PDB code: 1Q0D). (f). Trimer of αßɤ urease from Sporosarcina pasteurii (PDB code: 4CEU). The α, ß, and ɤ subunits are in magenta, blue, and cyan, respectively. Helix‐turn‐helix motif (residues 375–405) belonging to subunit α is highlighted in orange. (g). Closed conformation of LarA from Lactobacillus plantarium (PDB code: 5HUQ). The two domains are in orange and blue and the pincer nucleotide is in magenta. (h). Glyoxalase I dimer from E. coli (PDB code: 1F9Z). (i). Ni‐ARD monomer from Klebsellia oxytoca (PDB code: 1ZRR) α‐helices are in cyan and ß‐strands in magenta. In all structures, nickel ions are depicted as green spheres and FeS clusters are depicted in red and yellow spheres for iron and sulfur atoms, respectively

Figure 3

Active sites of Ni‐enzymes. S‐donors: comparison between natural sulfide nickelian mackinawite, greigite, and violarite and early nickel enzymes (adapted from Reference 46). Nickel and active site coordinating atoms are in spheres. Ni is in green, nitrogen in blue, sulfur in yellow, and oxygen in red. W, water molecule

Figure 4

Maturation of urease. In this mechanism, the nickel‐charged UreG dimer is recruited to form the activation complex with apo‐urease and UreF₂H₂. GTP hydrolysis promotes the nickel release for urease maturation (adapted from Reference 85)

Figure 5

Maturation of [NiFe]‐hydrogenase. The proposed mechanism for the enzyme biosynthesis is divided into three successive steps. 1. The Fe(CN)₂CO moiety is synthesized prior to its insertion into the enzyme. 2. Nickel is inserted directly into the enzyme (adapted from Reference 60). 3. The proteolysis of the C‐terminal tail is necessary for the enzyme activation step (adapted from Reference 64)

Figure 6

Maturation of ACS/CODH. (a) Proposed mechanism for CODH maturation: Fe and S atoms are first inserted to form a classical [Fe₄S₄] cluster. The following steps remain unclear to yield the active C‐cluster (adapted from Reference 77). (b) Proposed mechanism for ACS maturation (adapted from Reference 79)

Figure 7

Maturation of LarA and MCR. (a). Proposed mechanism for the biosynthesis of the nickel‐pincer nucleotide, followed by its incorporation into LarA (adapted from Reference 89). (b). Biosynthetic pathway of coenzyme F430 by the Cfb machinery (adapted from Reference 91) and proposed working model for MCR assembly (adapted from Reference 93)