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Originally published In Press as doi:10.1074/jbc.M609112200 on November 9, 2006

J. Biol. Chem., Vol. 282, Issue 2, 1066-1071, January 12, 2007
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Diatomic Ligand Discrimination by the Heme Oxygenases from Neisseria meningitidis and Pseudomonas aeruginosa*

Jonathan Friedman{ddagger}, Yergalem T. Meharenna{ddagger}, Angela Wilks§, and Thomas L. Poulos{ddagger}1

From the {ddagger}Departments of Molecular Biology and Biochemistry, of Physiology and Biophysics, and of Chemistry and the Center for Chemical and Structural Biology, University of California, Irvine, California 92697 and §Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201

Received for publication, September 26, 2006 , and in revised form, November 1, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS AND DISCUSSION
 REFERENCES
 
Heme oxygenases have an increased binding affinity for O2 relative to CO. Such discrimination is critical to the function of HO enzymes because one of the main products of heme catabolism is CO. Kinetic studies of mammalian and bacterial HO proteins reveal a significant decrease in the dissociation rate of O2 relative to other heme proteins such as myoglobin. Here we report the kinetic rate constants for the binding of O2 and CO by the heme oxygenases from Neisseria meningitidis (nmHO) and Pseudomonas aeruginosa (paHO). A combination of stopped-flow kinetic and laser flash photolysis experiments reveal that nmHO and paHO both maintain a similar degree of ligand discrimination as mammalian HO-1 and the HO from Corynebacterium diphtheriae. However, in addition to the observed decrease in dissociation rate for O2 by both nmHO and paHO, kinetic analyses show an increase in dissociation rate for CO by these two enzymes. The crystal structures of nmHO and paHO both contain significant differences from the mammalian HO-1 and bacterial C. diphtheriae HO structures, which suggests a structural basis for ligand discrimination in nmHO and paHO.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
 RESULTS AND DISCUSSION
 REFERENCES
 
Heme oxygenase (HO)2 catalyzes the oxidative degradation of heme to biliverdin, iron, and CO (Fig. 1). HO has been identified in a wide array of organisms, including mammals (1, 2), insects (3, 4), and photosynthetic organisms (5, 6). Of particular interest, HO is present in many pathogenic bacteria (7-10), including Neisseria meningitidis (11) and Pseudomonas aeruginosa (12). These pathogenic bacteria have developed sophisticated heme uptake systems that harness the iron from heme-containing proteins present in the host (13-15). The HO enzymes from N. meningitidis (nmHO) and P. aeruginosa (paHO) are both essential for the utilization of iron from imported heme, and the crystal structures of these two bacterial HO enzymes have now been solved (16, 17). Although most HOs hydroxylate exclusively the {alpha}-meso heme carbon (Fig. 1), paHO is unusual because the {gamma}-meso carbon is the predominate site of hydroxylation (18) even though the structure paHO is very much the same as other HOs. The difference in hydroxylation patterns is due to an ~100° rotation of the heme in paHO relative to other HOs which places the {gamma}-meso carbon at the same position in the active site as the {alpha}-meso carbon in other HOs (16).

The Fe(II) atom of the heme prosthetic group of heme proteins is an efficient binder of O2, NO, and CO, and the binding by heme proteins of these diatomic molecules is of critical importance to physiological processes such as respiration, vasodilation, and neurotransmission (19-21). A common feature shared by all heme proteins is the need to not only bind its target ligand but also to discriminate against the binding of heme ligands of similar size and shape. Fe(II) adducts of CO are normally linear because backbonding is optimized by the overlap of Fe(II) d-orbitals with the empty {pi}* orbitals of CO (22-24). In contrast, Fe(II)-NO and Fe(II)-O2 are naturally bent in order to maximize overlap with the occupied {pi}* electrons of the ligand with the dz2 iron orbitals. Thus, the intrinsic binding geometries of these ligands can be utilized by heme proteins to increase ligand discrimination (25, 26).

It has been suggested that ligand discrimination by globins results from the preferred ligand geometries of bound O2 and CO (27). The greater polarity of the bound O2 ligand also plays a role in enhancing the affinity of O2 relative to CO for both the globins and HO enzymes. The partition constant (M), defined as the ratio of the equilibrium association constants for CO and O2 (KCO/KO2), is ~30,000 for free heme, whereas that for sperm whale myoglobin is only ~40 and is further reduced to ~4 for human heme oxygenase (28, 29). The O2 affinities of mammalian HO-1 and HO-2 are 30–90-fold higher than those of mammalian myoglobins (28), whereas the O2 affinity of the bacterial HO from C. diphtheriae is 20-fold higher than that of myoglobin (29). This increased O2 affinity is largely due to a 100-fold slower rate of dissociation from HO relative to the globins. Thus, even though the inherent affinity of the ferrous heme for O2 is lower than that for CO, myoglobin and heme oxygenase clearly alter the binding characteristics of the heme, dramatically increasing the O2 affinity relative to CO. Here we report the kinetic rate constants for the binding of CO and O2 by the bacterial heme oxygenases, nmHO and paHO, and provide a structural basis for ligand discrimination.


   EXPERIMENTAL PROCEDURES
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
 REFERENCES
 
Preparation of Ligand-bound Heme Oxygenases—Expression, purification, and reconstitution of the recombinant nmHO and paHO with heme were carried out as described previously (11, 12). Spectral characterization and information on the stability of nmHO and paHO have been reported (11, 12). Ligand binding reactions were measured using stopped-flow and flash photolysis techniques as described previously (30, 31). The CO forms of the enzymes were prepared by diluting the ferrous form of the heme·HO complex into anaerobic buffer solutions containing known CO concentrations. Because of the rapid rate of autooxidation of ferrous iron, the oxygenated forms of the enzymes were made as follows. First, the ferric heme·HO complex was reduced with sodium dithionite in deoxygenated buffer. Then, the reduced form of the complex was loaded onto a column of Sephadex G-25 and eluted with buffer containing known oxygen concentrations. Formation of the complex and sample integrity were confirmed by optical absorption spectra recorded before and after flash photolysis measurements. All of the kinetic measurements were carried out in 20 mM Tris-HCl buffer, pH 7.5, at 20 °C. Stock solutions of O2, CO, and NO were prepared by equilibrating the buffer with 1 atm of the pure gas at room temperature. If required, saturated stock solutions (1300 µM O2, 1000 µM CO, and 1800 µM NO) were diluted with degassed buffer in gas-tight Sample-Lock Hamilton syringes.


Figure 1
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  		FIGURE 1.
Overall reaction catalyzed by heme oxygenase. HO enzymes have an increased binding affinity for O2 relative to CO. Such discrimination is critical to HO function because one of the main products of heme catabolism is CO. Oxidation of the heme substrate by nmHO occurs exclusively at the {alpha}-meso position (shown at top left), whereas paHO oxidizes both the beta- and {delta}-meso heme carbons.

 
Association Rate Constants—Oxygen association rate constants were measured by laser flash photolysis using a pulsed dye laser system fitted with a Quantel Brillian B Nd:YAG laser. Solutions were irradiated at {lambda} = 540 nm (beta-band of heme) with a pulse of 10 ns and monitored at {lambda} = 434 nm (Fe2+ soret peak). CO association rate constants were measured by stopped-flow kinetics using an Applied Photophysics SX18MV-R. Solutions were also monitored at {lambda} = 434 nm. Final protein concentrations for each set of experiments were 10 µM. Time courses are the average of five traces, and the observed rates for O2 and CO binding by nmHO and paHO were obtained by fitting the average traces to a single exponential expression. Second-order association rate constants were obtained from the slopes of the linear plots of the observed pseudo-first-order rate constants versus ligand concentration.

Dissociation Rate Constants—Dissociation rate constants for both O2 and CO were measured directly by carrying out replacement reactions with an Applied Photophysics SX18MV-R. The ligands of a 10 µM solution of the O2- and CO-bound forms of the HO enzymes were replaced by a high concentration of displacing ligand (500 µM CO and 900 µM NO, respectively). Solutions were measured at {lambda} = 410 nm and {lambda} = 420 nm in order to follow the absorbance changes due to the dissociation of O2 and CO, respectively. The dissociation rate constants were then calculated from the expressions Formula and Formula. Because Formula for all heme proteins, the observed replacement rate constant (kobs) was directly equal to the CO dissociation rate constant (kCO).

Molecular Dynamics—Molecular dynamics simulations were carried out with Amber 8.0. Heme parameters were provided by Dr. Dan Harris (Molecular Research Institute). Partial charges for the heme and CO were taken from the ferrous·CO complex provided by Dr. John Straub (Boston University). The crystal structures for CO complexes of rat HO-1 (1IX4) and nmHO (1P3V) were stripped of crystallographically defined water molecules except for those in the active site near the bound CO. The solvent-stripped structure was solvated with water molecules within a 30 Å radius of the CO molecule. The entire solvated protein was energy minimized as follows. First, water and H atoms were allowed to move in a short 10-ps low temperature (50 °C) MD simulation followed by 500 cycles of energy minimization for both protein and solvent. Second, both protein and solvent were allowed to move in a 10-ps 50 °C MD simulation followed by 500 cycles of energy minimization. Finally, a 2-ns MD simulation was carried out at 300 °C. Residues within a 20 Å sphere surrounding the CO were allowed to move. Coordinate sets were saved every 10 ps, giving a total of 200 coordinate sets. During all minimizations and dynamics runs the CO molecule was constrained to the crystallographic coordinates. This was done to avoid ambiguity in modeling the Fe-C-O bond angle and tilt.


Figure 2
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  		FIGURE 2.
Kinetics of CO and O2 ligand binding by bacterial heme oxygenases. Panels A–D are representative raw stopped-flow (A, B, D) or flash photolysis (C) traces for association and dissociation reactions with nmHO. For CO (A) and O2 (C) association reactions the concentration of ligand was 400 and 520 µM, respectively. E, observed rate dependence for the association reaction of CO with the heme complex of nmHO (closed symbols) and paHO (open symbols) measured by stopped-flow kinetics. F, observed rate dependence for the association reaction of O2 with the heme complex of nmHO (closed symbols) and paHO (open symbols) measured by laser flash photolysis.

 

   RESULTS AND DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS AND DISCUSSION
REFERENCES
 
Ligand Binding and Dissociation Kinetics—The association and dissociation rate constants for the binding of CO and O2 by nmHO and paHO are compared with those of myoglobin, mammalian HO-1, and bacterial cdHO, and protoheme in Table 1. The CO and O2 equilibrium constants (KCO and KO2) and the ratios of equilibrium constants (KCO/KO2) for nmHO and paHO are also provided in Table 1.


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  		TABLE 1
Association and dissociation rate constants for nmHO and paHO Data for myoglobin, HO-1, cdHO, and protoheme were taken from Migita et al. (28), Unno et al. (29), and Tani et al (41).

 
Bimolecular rebinding of O2 by nmHO and paHO after flash photolysis is monophasic, and the observed rates show a first-order dependence on the O2 concentration. The association rate constants for O2 binding by nmHO and paHO are 5.0 and 4.5 µM-1 s-1, respectively. These values are ~4-fold smaller than that of myoglobin but very similar to both the mammalian and bacterial HO enzymes. The CO association reactions of both the nmHO and paHO heme complexes are also monophasic, with the observed rates showing a linear dependence on the CO concentration. Although the time courses for the binding of CO by HO-1 and cdHO were moderately biphasic and could be fit to a two-exponential expression (29), the time courses for CO binding by nmHO and paHO were observed to be monophasic and were fit to a single exponential expression at several different CO concentrations. The association rate constants for CO binding by nmHO and paHO are 1.10 and 0.90 µM-1 s-1, respectively. These values are similar to that of myoglobin, as well as those of HO-1 and cdHO. Sample traces for the CO and O2 association reactions are provided in Fig. 2, A and C, respectively. The second-order association rate constants for the binding of CO and O2 by nmHO and paHO were obtained from the slopes of the linear plots of the observed rate constants (kobs) versus ligand concentration (Fig. 2, E and F). The O2 dissociation rate constants for nmHO and paHO are 1.5 and 1.7 s-1, respectively. These data indicate that the dissociation rate constants for O2 binding by nmHO and paHO are ~14-fold slower than that of myoglobin but are ~7-fold faster than those of mammalian HO-1 and bacterial cdHO. The CO dissociation rate constants for nmHO and paHO are 0.16 and 0.12 s-1, respectively. The dissociation rate constants for CO binding by nmHO and paHO are ~6-fold faster than that of myoglobin but are ~22-fold faster than those of HO-1 and cdHO. Sample traces for the CO and O2 dissociation reactions are provided in Fig. 2, B and D, respectively.


Figure 3
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  		FIGURE 3.
Crystal structure of CO and NO complexes for rat HO-1 and nmHO. The Protein Data Bank codes are in parentheses.

 
The oxygen equilibrium constants (KO2) for nmHO and paHO are 3.3 and 2.6 µM-1, respectively, which are ~3-fold greater than that of myoglobin but ~8-fold smaller than those of HO-1 and cdHO. The CO equilibrium constants (KCO) for nmHO and paHO are 6.9 and 7.5 µM-1, respectively, which are ~5-fold smaller than that of myoglobin but are ~17-fold smaller than those of HO-1 and cdHO. It should be noted that although the CO and O2 equilibrium constants (KCO and KO2) for nmHO and paHO are smaller than those of HO-1 and cdHO, the ratios of equilibrium constants (KCO/KO2) for nmHO and paHO are 2 and 3, respectively, which are similar to those of HO-1 and cdHO. The smaller CO and O2 affinities by nmHO and paHO are largely due to the much faster dissociation rate constants for these enzymes compared with HO-1 and cdHO.

Structural Basis for Ligand Discrimination—The problem in understanding ligand discrimination is illustrated in Table 1. Protoheme binds CO ~30,000-fold more tightly than O2 but only 40-fold more tightly in myoglobin. Steric factors were long thought to be the predominant structural underpinning of such ligand discrimination in heme proteins. Early on, Collman et al. (32) proposed that a strategically placed distal histidine in myoglobin could accommodate a bent O2 ligand but would inhibit the binding of a normally linear CO ligand. However, in recent years structural, spectroscopic, and theoretical studies have revealed the importance of electrostatic interactions for diatomic ligand discrimination (25, 33, 34). In particular, it has been shown that the H-bond between the distal His in myoglobin and O2 is quite important in controlling O2 affinity (35).

The HO crystal structures show that steric crowding is an important factor in HO although electrostatics also is quite important. Dioxygen-bound cdHO has two strong hydrogen bonds that can preferentially stabilize the highly polar Fe·O2 complex (29). One interaction is with the amide NH of Gly-139, and the other is with the distal pocket water molecule. Mutagenesis studies have also demonstrated that increasing the strength and number of hydrogen bonds donated from the distal pocket amino acids to the iron-bound O2 decreases the rate of O2 dissociation from myoglobin (36-38). Therefore, the more extensive H-bonding in HO-1 compared with myoglobin explains why koff of O2 is slower in HO-1 and thus is a major contributing factor in ligand discrimination.


Figure 4
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  		FIGURE 4.
Panels A and C are the average MD structures (green) taken over the last 1 ns of the simulation (100 structures) superimposed on the crystal structures (cyan). The key water molecule interacting with CO is indicated by green (MD) and red (crystal) spheres. Panels B and D are the average MD structures showing key distances indicated by the dashed lines.

 
Whether or not this view holds with all HOs will require additional structures of oxy complexes, but unfortunately obtaining such structures is very difficult. However, NO is a good mimic of O2 because, like O2, NO prefers a bent geometry. Moreover, the structure of the rat HO-1·NO (39) complex exhibits a very similar H-bonding pattern as the cdHO·O2 complex (Fig. 3D). Thus, a comparison between various CO and NO complexes provides some insights on O2/CO discrimination. Currently, the only two heme oxygenases that have crystal structures available for both the CO- and NO-bound forms are those of nmHO and rat HO-1 (39, 40). As shown in Fig. 3D, the NO has three H-bonding partners, the peptide NH of Gly-143 and a water molecule which, as already noted, is very similar to the cdHO·oxy complex (29). The situation with nmHO is slightly different. In this case the NO forms only one H-bond, with the active site water. The peptide NH group of Gly-120 (Fig. 3B) is too far and geometry not optimal for good H-bonding. If, as we expect, the oxy complex is similar, then the missing H-bond in nmHO compared with HO-1 helps to explain why koff for O2 is faster in nmHO than in HO-1 or cdHO.

The more significant difference between nmHO and HO-1 or cdHO is that koff for CO is ~18 times faster, indicating that the nmHO·CO complex is less stable that in HO-1. HO-1 undergoes a fairly large structural change in response to CO binding, whereas nmHO does not. To accommodate the CO ligand, which prefers a linear Fe-C-O geometry, the distal helix in HO-1 shifts by ~1.0 Å and the CO-bound heme shifts by ~1.0 Å in the opposite direction. The bent NO, however, leads to very little change.

In sharp contrast, the nmHO structure does not change when CO binds. As a result, the CO may experience less favorable electrostatic interactions than in HO-1. More specifically, in HO-1·CO the active site water is 2.9 Å from the CO whereas this distance is 3.1 Å in nmHO (Fig. 3, A and C). In addition, the CO is very close, 2.7 Å, to the carbonyl oxygen of Ser-117 whereas the corresponding distance is 2.9 Å in HO-1 (Fig. 3, A and C). A 0.2 Å difference is small and probably within the margin of error in comparing two structures. Thus, it is difficult to conclude that differences in steric crowding are the structural basis for the differences in CO koff. Here is where the molecular dynamics simulations provided some insights that point toward electrostatics as being an important factor in controlling the stability of the CO complex. The average MD structure (average of 100 structures) taken over the last 1 ns of the simulation superimposed on the crystal structures is shown in Fig. 4. Also shown in panels B and D are the average MD structures together with key distances. There are two important differences between nmHO and HO-1. First, note that in HO-1 the peptide carbonyl O atom of Gly-139 is tied up in a helical H-bond with Gly-144 (Fig. 4B) whereas the corresponding carbonyl O atom in nmHO (Ser-117) is not (Fig. 4D). As a result, the partial negative charge on the carbonyl O atom of Ser-117 in nmHO is not attenuated by H-bonds, thus providing greater electrostatic destabilization of the CO O atom than in HO-1. Second, the water near the CO in HO-1 is closer to the CO than in nmHO, thus providing greater electrostatic stabilization of the CO O atom. Over the 2-ns simulation the water-CO distance is 4.61 ± 0.97 Å in HO-1 and 5.83 ± 1.29 Å in nmHO-1. There is a fair amount of fluctuation owing to large movement of solvent as expected, but it is clear that the CO is better solvated in HO-1. Thus, less electrostatic stabilization of and greater electrostatic repulsion of CO in nmHO can help to explain the faster koff for CO.

One problem with this argument is that CO is normally considered to be the least polar of heme diatomic ligands and, as such, electrostatics should not play that important a role in CO binding. However, electrostatic control of CO binding is supported by model heme studies. One comprehensive study on CO- and O2-bound twin-coronet porphyrins (TCPs) established that CO/O2 ligand discrimination may be controlled by the polar effects exerted by overhanging hydroxyl groups (41). Specifically, the TCP·O2 complex was stabilized by hydrogen bonding with two overhanging hydroxyl groups, whereas the TCP·CO complex was destabilized because of suppression of {pi} backbonding from the iron atom to bound CO. The decrease in backbonding was caused by strong negative electrostatic interactions of bound CO with the lone pairs of the hydroxyl groups in the distal pocket, which resulted in an increase in the dissociation rate of CO from TCP compared with chelated protoheme (41). These model heme studies thus support the view that the reason nmHO exhibits a slower CO koff than HO-1 is due to less favorable electrostatic stabilization of the CO complex compared with HO-1.


   FOOTNOTES
 
* 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. Back

1 To whom correspondence should be addressed. Tel.: 949-824-7020; Fax: 949-824-3280; E-mail: poulos{at}uci.edu.

2 The abbreviations used are: HO-1, mammalian heme oxygenase isozyme-1; nmHO, N. meningitidis heme oxygenase; paHO, P. aeruginosa heme oxygenase; cdHO, C. diphtheriae heme oxygenase; CO, carbon monoxide; NO, nitric oxide; O2, dioxygen; Heme, Fe-protoporphyrin IX; TCP, twin-coronet porphyrin; MD, molecular dynamics. Back



   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS AND DISCUSSION
 REFERENCES
 

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