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J. Biol. Chem., Vol. 279, Issue 14, 13962-13967, April 2, 2004

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The Functional Role of the Binuclear Metal Center in D-Aminoacylase

ONE-METAL ACTIVATION AND SECOND-METAL ATTENUATION^*

Wen-Lin Lai, Lien-Yang Chou, Chun-Yu Ting, Ralph Kirby¶, Ying-Chieh Tsai, Andrew H.-J. Wang||, and Shwu-Huey Liaw¶**

From the Structural Biology Program, Institute of Biochemistry, ^¶Faculty of Life Science, National Yang-Ming University, Taipei 11221, Taiwan, the ^||Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan, and the ^**Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan

Received for publication, August 11, 2003 , and in revised form, January 20, 2004.

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Our structural comparison of the TIM barrel metal-dependent hydrolase(-like) superfamily suggests a classification of their divergent active sites into four types: -binuclear, -mononuclear, -mononuclear, and metal-independent subsets. The D-aminoacylase from Alcaligenes faecalis DA1 belongs to the -mononuclear subset due to the fact that the catalytically essential Zn²⁺ is tightly bound at the site with coordination by Cys⁹⁶, His²²⁰, and His²⁵⁰, even though it possesses a binuclear active site with a weak binding site. Additional Zn²⁺, Cd²⁺, and Cu²⁺, but not Ni²⁺, Co²⁺, Mg²⁺, Mn²⁺, and Ca²⁺, can inhibit enzyme activity. Crystal structures of these metal derivatives show that Zn²⁺ and Cd²⁺ bind at the ₁ subsite ligated by His⁶⁷, His⁶⁹, and Asp³⁶⁶, while Cu²⁺ at the ₂ subsite is chelated by His⁶⁷, His⁶⁹ and Cys⁹⁶. Unexpectedly, the crystal structure of the inactive H220A mutant displays that the endogenous Zn²⁺ shifts to the ₃ subsite coordinated by His⁶⁷, His⁶⁹, Cys⁹⁶, and Asp³⁶⁶, revealing that elimination of the site changes the coordination geometry of the ion with an enhanced affinity. Kinetic studies of the metal ligand mutants such as C96D indicate the uniqueness of the unusual bridging cysteine and its involvement in catalysis. Therefore, the two metal-binding sites in the D-aminoacylase are interactive with partially mutual exclusion, thus resulting in widely different affinities for the activation/attenuation mechanism, in which the enzyme is activated by the metal ion at the site, but inhibited by the subsequent binding of the second ion at the site.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

To date, crystal structures of 14 members in the superfamily have been determined. As more structures are solved, more divergences in the metal centers and in the -strand packing of the TIM barrel are observed (Fig. 1). Based on the binding site(s) of the catalytically essential metal ion(s), we classify these members into four types: -binuclear (), -mononuclear (), -mononuclear (), and metal-independent subsets. Phosphotriesterase (homology protein), urease, dihydroorotase, renal dipeptidase, isoaspartyl didpeptidase, and dihydropyrimidinase comprise the subset (5–15). Murine adenosine deaminase and Escherichia coli cytosine deaminase belong to the subset (16, 17). D-Aminoacylase belongs to the subset due to the essential Zn²⁺ binding tightly at the site, even though it possesses a weak binding site (3). In contrast, the activity assay and the crystal structure of uronate isomerase show that this enzyme does not display any specific metal requirement and thus belongs to the metal-independent subset (18, 19).

View larger version (43K): [in this window] [in a new window]   FIG. 1. Comparison of human renal dipeptidase (red, Protein Data Bank code 1ITU [PDB] ), E. coli phosphotriesterase homology protein (blue, Protein Data Bank code 1BF6 [PDB] ), D-aminoacylase (green), T. maritima NAGA (magenta, Protein Data Bank code 1O12 [PDB] ), and T. maritima TatD (cyan, Protein Data Bank code 1J6O [PDB] ), with a close view of the divergent -strand packing of the TIM barrel (A) and the binuclear metal centers (B). The residue numbering is labeled in the same color for each protein. The site is constituted by the first two conserved histidines from a common HXH motif at the 1 strand, a bridging ligand, and/or the conserved aspartate at the 8 strand, where the site is coordinated by the last two conserved histidines at the 5 and 6 strands and the bridging ligand. An assigned water molecule at the site in the T. maritima TatD has close contacts with the conserved ligands Glu91 O2 (2.02 Å), His127 N1 (2.21 Å), His152 N2 (2.33 Å), and two ordered water molecules (2.44 and 2.48 Å), suggesting the possibility of a magnesium ion. Most bridging residues are located at the 4 strand, except for the glutamates in human renal dipeptidase and NAGAs at the 3 strand and the cysteine in D-aminoacylase at the 2 strand. The second conserved histidine is replaced by an aspartate (Asp22) in renal dipeptidase. The shift in the sequence position by one residue leads to the His198 of renal dipeptidase and the His176 of T. maritima NAGA using the N2 instead of N1 atom for the metal ligation and causes larger structural differences at Glu125 of E. coli phosphotriesterase homology protein, Glu91 of TatD, His219 of renal dipeptidase, and His152 of T. maritima TatD.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Structural similarity search and subsequent structural comparisons were carried out by DALI (22), VAST (23),and INSIGHT II (Molecular Simulation Inc.). The recombinant protein of DA1 D-aminoacylase was expressed, isolated, and crystallized as described previously (24). The enzyme activity was measured using N-acetyl-D-methionine as substrate coupled to a D-amino acid oxidase enzyme assay (25). Crystals of H220A and D366A mutants were grown as described for the native enzyme. The different metal derivatives were prepared by soaking crystals of the wild-type and mutant enzymes in a solution containing 10 µl of divalent cation solution (100–200 mM) and 10 µl of reservoir solution containing 25–30% polyethylene glycol 4000, 0.1 M sodium citrate (pH 5.6), and 0.2 M ammonium acetate. The native protein contains one zinc ion tightly bound at the site, even though no metal ions were added either during protein purification or crystallization (3). Neither extensive dialysis of the protein solution against 100 mM EDTA in 50 mM Tris-HCl (pH 7.8) buffer nor soaking of the crystals with 100 mM EDTA in the crystallization solution could remove this bound zinc ion. Therefore, zinc ion is believed to bind tightly at the site in the metal derivatives as in the native enzyme.

The x-ray data were collected by using either an in-house radiation or synchrotron radiation and then processed using the program HKL (26). The crystals belong to the space group P2₁2₁2₁, with one molecule in an asymmetric unit. The crystal structures of the metal derivatives and the mutants were solved by molecular replacement. The initial model was constructed starting with the refined coordinates of the wild-type protein at 1.5-Å resolution (Protein Data Bank code 1M7J [PDB] ). The mutated residue (Asp³⁶⁶ or His²²⁰), the bound zinc ions, and all water molecules were omitted from the initial model. The first simulated annealing omit maps clearly indicated the presence of the bound metal ions and the position of the missing residue. All structures were refined using CNS monitored by the free R factor and the quality of the electron density maps (27). The refinement parameters are presented in Table I. Figs. 1 and 3D were generated by INSIGHT II (Molecular Simulation Inc.), Fig. 3, A–C, by BOBSCRIPT (28).

View larger version (28K): [in this window] [in a new window]   FIG. 3. The metal centers. A, the Fo - Fc electron density maps of the native enzyme in complex with 100 mM ZnCl2 contoured at 15 level and shown in magenta, with 50 mM CdCl2 contoured at 15 level and shown in cyan, and with 100 mM CuCl2 contoured at 18 level and shown in green. The metal ligands are shown as a ball-and-stick representation, with the Zn2+ and Cu2+ ions as magenta and green spheres, respectively. Zn2+ and Cd2+ bind at the subsite, where Cu2+ binds at the 2 subsite. B, the 2Fo - Fc electron density maps of the H220A mutant contoured at 2.5 level and shown in cyan, and the difference map for the zinc ion contoured at 15 level and shown in magenta. The endogenous zinc ion binds at the 3 subsite instead of the site in this mutant. C, the 2Fo - Fc electron density map of the D366A mutant contoured at 2.5 level and shown in cyan, and the difference map for the zinc ion in complex with 100 mM ZnCl2 contoured at 15 level and shown in magenta. The additional zinc ion binds at the 4 subsite. D, superposition of the native enzyme with 100 mM ZnCl2 in blue, the native enzyme with 100 CuCl2 in green, the H220A mutant in yellow, and the D366A mutant with 100 mM ZnCl2 in red. The different metal coordination is carried out by small shifts in the side chains of ligands and small movements of the metal ions.

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

View larger version (16K): [in this window] [in a new window]   FIG. 2. A, attenuation of the D-aminoacylase activity by added ZnCl2 (•), CdCl2 (), and CuCl2 (). For the inhibition assay, the indicated divalent cation concentrations were incubated with 4–5 nM enzyme for 10 min at 37 °C in 50 mM Tris-HCl (pH 7.8), and the residual activity was then measured. Data points are the average of five assays with the standard deviations below 10%. B, plot of 1/velocity (1/V) versus 1/[N-acetyl-D-methionine] (1/S) in the presence of various CdCl2 levels of 0 µM (•), 30 µM (), 60 µM (), 90 µM (), 120 µM (), and 150 µM (). Assays were carried out in the presence of substrate concentrations of 0.4, 0.6, 0.8, 1.0, 1.2, 1.5, and 2.0 mM.

View this table: [in this window] [in a new window]   TABLE III The geometries of sites

Cysteine residues have never been found to serve as ligands in the cocatalytic zinc-binding sites with the possible exception of the zinc-dependent -lactamases (32). Instead aspartate and histidine predominate as ligands in cocatalytic zinc sites, and a bidentate carboxylate group is the predominant bridging ligand. Once a cysteine binds to metal ions, its sulhydryl side chain is considered to be deprotonated and to have a more favorable charge-charge electrostatic interaction. Because Cys⁹⁶ contributes most of its charge to interact with the tightly bound ion, Cys⁹⁶ may not interact with the second metal ion strongly. As a result, the enzyme utilizes His⁶⁷, His⁶⁹, and Asp³⁶⁶ for chelation of additional Zn²⁺ and Cd²⁺. On the other hand, Cu²⁺ is a "soft" ion and prefers soft ligands, with sulfur and nitrogen being the most preferred coordinating atoms. Protein Data Bank surveys of copper-binding sites have shown that very seldom is a copper ion ligated by acidic residues (33, 35). Therefore, the additional Cu²⁺ chooses His⁶⁷, His⁶⁹, and Cys⁹⁶ as its ligands.

The Inactive H220A Mutant—Unexpectedly, the difference electron density maps showed that in the H220A mutant the endogenous zinc ion no longer binds at the site, instead it is tetrahedrally coordinated by His⁶⁷, His⁶⁹, Cys⁹⁶, and Asp³⁶⁶ at the ₃ subsite (Fig. 3B). The ₃ subsite is located almost midway between the ₁ and ₂ sites (Table III). Elimination of the enzyme activity by the substitution of His²²⁰ with alanine may be due to a lack of the ion, suggesting that the ion is indeed required for the catalysis. The metal coordination in the H250N mutant is expected to be similar to that in the H220A mutant because both His²²⁰ and His²⁵⁰ ligate the ion, and the H220A and H250N mutants bind approximately half the normal complement of zinc ion (25, 30).

The much stronger electron density peak and lower B-factor of the zinc ion in the H220A mutant (20.5 Ų for the zinc ion and an average value of 15.4 Ų for all protein atoms) than the proposed zinc ion at the ₁ subsite in the native enzyme (51.5 Ų for the zinc ion and an average value of 9.3 Ų for all protein atoms) show that elimination of the ion enhances the binding affinity of the ion. This enhancement suggests that the and sites are interactive with partially mutual exclusion. In the native enzyme, Cys⁹⁶ commits most of its charge to interact with the ion and thus could not interact with the ion strongly, resulting in different metal-binding affinities. Once the site is destroyed, Cys⁹⁶ could contribute its charge to interact with the ion and thus enhance metal affinity. This unusual bridging Cys⁹⁶ has been shown to contribute the most toward the interactions with the metal ions among the ligands, because the C96A mutant shows very little zinc-binding ability, 0.2 g·atom/mol of enzyme (25). The less active C96D mutant also demonstrates the uniqueness of this cysteine residue.

The Inactive D366A Mutant—The electron density maps showed that the tetrahedral arrangement of the zinc ion in the D366A mutant is maintained as in the native enzyme (Fig. 3C). Replacement of Asp³⁶⁶ with alanine does not induce any significant conformational change, but it does abolish enzyme activity, perhaps due to its action via proton transfer as a general base. A similar coordination geometry of the zinc ion is expected as well for the His⁶⁷ and His⁶⁹ mutants because these three residues do not chelate the ion, and neither the H67N nor the D366A mutant shows a significant drop in zinc binding (25, 30). In D366A mutant, additional Cu²⁺ binds at the ₂ subsite, the same as in the wild-type protein, while Zn²⁺ binds weakly at another site (₄) surrounded by His⁶⁷, His⁶⁹, Cys⁹⁶, and ACT1 (Table III, Fig. 3D).

A comparison of the crystal structures presented here reveals that the spatial locations of all protein residues are virtually identical, suggesting that the His²²⁰ mutant, the Asp³⁶⁶ mutant, and the metal binding to the enzyme do not significantly alter the three-dimensional structure (Fig. 3D). The differences in metal coordination are achieved by small movements of the metal ions and small shifts in the side chains of ligands to accommodate the metal binding. These results seem to be in agreement with the entatic state theory proposed by Williams, in which the metal site in a metalloprotein is configured by the protein matrix (36). The contrast between virtually identical sites and conformationally variable sites with a looser arrangement of ligands is consistent with their different affinities.

A Metal Inhibition Mechanism—There are two possible mechanisms for the inhibition effect of the metal ion (Fig. 4). First, the proton dissociation energy of histidine has been shown to drop significantly upon metal ion binding, due to stabilization of the negatively charged imidazolate anion by metal dication through charge-charge interactions and charge transfer (37). Therefore, ligation of the ion by the highly conserved residues His⁶⁷, His⁶⁹, and Asp³⁶⁶ would lower their pK_a and thus down-regulate their ability to efficiently carry out the proton transfer and intermediate stabilization, resulting in a reduction in k_cat. Second, the putative active site water molecule, which is likely to be present at the product acetate ACT1 O¹ position, lies significantly closer to the zinc ion at the ₁ subsite (1.95 Å) than that at the site (2.84 Å). This is one striking difference between the active site here and those in other binuclear zinc hydrolases such as the members, where the water/hydroxide ion is almost symmetrically located between the two metal ions (5–15). Therefore, the inhibitory metal ion at the site may hold the active site water tightly and thus perturb the stereochemical arrangements required for enzyme catalysis as it does in bovine carboxypeptidase A (38). The much stronger inhibition by Zn²⁺ and Cd²⁺ than Cu²⁺ may be due to Asp³⁶⁶, an important residue for the proton shuttle, and the active site water molecule being closer to the ₁ subsite than the ₂ subsite (2.61 Å).

View larger version (18K): [in this window] [in a new window]   FIG. 4. The proposed mechanisms for catalysis (A) and metal attenuation (B). The numbers shown indicate the interatomic distances in angstroms. Asp366 maybe with assistance from His67 and His69, is responsible for the proton transfer from the water molecule to the amide nitrogen (3). The presence of the inhibitory metal ion at the 1 site might lower the pKa values of its ligand residues, His67, His69, and Asp366, and/or hold the active site water to perturb the proton shuttle and intermediate stabilization.

As mentioned above, NAGAs and TatD DNases have distinct amino acid triplets for the conserved HXH, but there is similarity in the pattern of evolution. Sequence analysis of the HXH and GXN groups of TatD DNases shows that the former are solely present in the Eubacteria, while the latter are present in the Eubacteria, Archeae, and Eukaryotes. This would suggest that the latter is a more ancient form of the enzyme, which does not require the involvement of metal regulation. In some Eubacteria, the GXN enzyme is present in parallel with a HXH enzyme, suggesting a distinct functional difference that may be related to the presence of metal regulation at the active site. The GXN enzyme group of the Eubacteria is also generally Gram-negative proteobacteria having a close environmental relationship with Eukaryotes, and thus it is possible that the presence of this enzyme in these bacteria represent a horizontal transfer from Eukaryotes some time after the split of the three Kingdoms. Thus metal-based regulation of the active site in the HXH enzymes may have a particular function in Eubacteria and the need for an enzyme that is not subject to such regulation may be niche specific. For example, fluctuations in environmental metal content in Eukaryotes will generally be less than for free living bacteria. A similar pattern between bacteria and eukaryotes occurs for NAGAs, and thus it is possible that similar evolution pressures have resulted in a similar pattern of metal regulation between these two enzyme groups.

Inhibition by Excess Zinc Ion in Other Metalloenzymes—The crystal structures of thermolysin and carboxypeptidase A, main representatives of two large superfamilies, endo- and exoproteases, in the presence of excess zinc also show second inhibitory zinc-binding sites at the active site (38, 39). Both inhibitory zinc ions are also located in close proximity to the essential zinc (3.2 and 3.3 Å). The inhibitory zinc in thermolysin sterically excludes the substrate, whereas that in carboxypeptidase A holds the active site water molecule. Despite the great differences in overall folding and active-site topologies of the proteases and D-aminoacylase, their inhibitory zinc-binding sites share some common features with the cocatalytic zinc sites (32), in which the metal ions are in close proximity and bridged by external ligands (water, hydroxyl, acetate) and/or protein residues. Since zinc is the second-most abundant transition metal in living organisms after iron, it is quite possible that inhibitory zinc ions may be involved in important physiological functions and this should not be neglected.

Conclusions—The divergences of the metal centers and the -strand packing in the TIM barrel metal-dependent hydrolases illustrate the structural plasticity for the functional diversity in the superfamily. The present kinetic and structural studies of the A. faecalis DA1 D-aminoacylase suggest that the binuclear metal center in this -mononuclear member is responsible for an "activation/attenuation" mechanism, whereby the enzyme is activated by the Zn²⁺ ion at the site but inhibited by the subsequent binding of a second metal ion at the site.

	FOOTNOTES

 
The atomic coordinates and structure factors (codes 1V51, 1RK6, 1RJP, 1V4Y, 1RJQ, 1RJR, and 1RK5 (see Table I)) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Science Council Grant NSC 92-2311-B-010-010. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to the work.

To whom correspondence should be addressed: Dept. of Life Science, National Yang-Ming University, Taipei 11221, Taiwan. Tel.: 886-2-2826-7278; Fax: 886-2-2820-2449; E-mail: shliaw{at}ym.edu.tw.

¹ The abbreviation used is: NAGA, N-acetylglucosamine-6-phosphate deacetylase.

	ACKNOWLEDGMENTS

 
The synchrotron radiation experiments were performed at the National Synchrotron Radiation Research Center (NSRRC), Taiwan, at the Photon Factory, Tsukuba, Japan, and at the SPring-8, Sayo, Japan.

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TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 

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