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Non-Enzymatic and Enzymatic Hydrolysis of Alkyl Halides

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Non-Enzymatic and Enzymatic Hydrolysis of Alkyl Halides Proc. Natl. Acad. Sci. USA Vol. 94, pp. 8417–8420, August 1997 Biochemistry Non-enzymatic and enzymatic hydrolysis of alkyl halides: A haloalkane dehalogenation enzyme evolved to stabilize the gas-phase transition state of an SN2 displacement reaction FELICE C. LIGHTSTONE,YA-JUN ZHENG,ANDREAS H. MAULITZ, AND THOMAS C. BRUICE* Department of Chemistry, University of California, Santa Barbara, CA 93106 Contributed by Thomas C. Bruice, May 23, 1997 ABSTRACT The semiempirical PM3 method, calibrated reactions with the haloalkane dehalogenase of Xanthobacter against ab initio HFy6–311G(d) theory, has been used to autothropicus meet these criteria (8). elucidate the reaction of 1,2-dichloroethane (DCE) with the Dehalogenation enzymes have attracted considerable atten- carboxylate of Asp-124 at the active site of haloalkane deha- tion owning to the potential of applying these enzymes to the logenase of Xanthobacter autothropicus. Asp-124 and 13 other treatment of halogenated hydrocarbon-contaminated soil and amino acid side chains that make up the active site cavity water supplies (9–11). Haloalkane dehalogenase is of partic- (Glu-56, Trp-125, Phe-128, Phe-172, Trp-175, Leu-179, Val- ular interest because it catalyzes hydrolysis of alkyl halides 219, Phe-222, Pro-223, Val-226, Leu-262, Leu-263, and His- without requiring any cofactors or metal ions (8). The enzy- 289) were included in the calculations. The three most signif- matic hydrolysis of alkyl halides to the corresponding alcohols icant observations of the present study are that: (i) the DCE follows a two-step process, which involves the formation of an substrate and Asp-124 carboxylate, in the reactive ES com- alkyl-enzyme ester intermediate (12–14). Our interest is in the plex, are present as an ion-molecule complex with a structure initial step of the enzymatic-dehalogenation reaction, which similar to that seen in the gas-phase reaction of AcO2 with involves a nucleophilic attack of the carboxylate group of DCE; (ii) the structures of the transition states in the gas- Asp-124 on the halogen-bearing carbon, displacing the chlo- ride via an S 2-displacement reaction (Scheme1). From ex- phase and enzymatic reaction are much the same where the N amination of the x-ray crystallographic structure of the ES structure formed at the active site is somewhat exploded; and complex, Verschueren et al. (12–14) observed the indole NH (iii) the enthalpies in going from ground states to transition groups of Trp-125 and Trp-175 to be in position to hydrogen states in the enzymatic and gas-phase reactions differ by only bond to the leaving chloride and proposed this to be assisting a couple kcalymol. The dehalogenase derives its catalytic power from: (i) bringing the electrophile and nucleophile together in a low-dielectric environment in an orientation that allows the reaction to occur without much structural reorga- nization; (ii) desolvation; and (iii) stabilizing the leaving chloride anion by Trp-125 and Trp-175 through hydrogen bonding. For a catalytic reaction, knowledge of the structure of the critical transition state (TS) tells much about the means of catalysis. This is particularly so in the case of enzyme catalysis, considering the school of thought that enzyme catalysis is due to transition-state stabilization (1–4). Even though experimen- tal techniques such as x-ray diffraction and NMR have pro- vided and will continue to provide valuable structural infor- mation concerning the enzyme–substrate (ES), enzyme– intermediate, and enzyme–product complexes, it is highly unlikely that experimental techniques will ever allow direct observation of the transition state in an enzymatic reaction SCHEME 1 because of the extremely short life time of the transition state. in departure of Cl2 from the haloalkane. This feature has since An approach to characterizing a TS at the active site of an been confirmed by other experimental studies (15). The enzyme is to use quantum mechanical theory (5–7). To test this simplicity of the bimolecular S 2 displacement of Cl2 from a procedure, the following criteria must be met. First, for the N primary haloalkane by a carboxylate anion allows the com- theoretical results to be meaningful, the method should be able parison of the transition states for such a displacement in to treat at least the amino acid residues that line the active site non-enzymatic and enzymatic reactions. Using ab initio and of the enzyme. Second, the enzyme and the substrate must be semiempirical molecular orbital theory, the non-enzymatic small in size. Third, for the sake of simplicity, the reaction reaction of Eq. 1 has recently been studied in both gas phase being studied should consist of a single step, thereby obviating and in solution in this laboratory (16). Here we report the intermediates. Fourth, a well studied enzyme must be chosen results of an investigation of the enzymatic reaction. so that the theoretical results can be validated. The catalytic 2 2 CH3CO2 1 ClCH2CH2Cl 3 CH3CO2OCH2CH2Cl 1 Cl [1] The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in Abbreviations: ES, enzyme substrate; TS, transition state; DCE, accordance with 18 U.S.C. §1734 solely to indicate this fact. 1,2-dichloroethane. © 1997 by The National Academy of Sciences 0027-8424y97y948417-4$2.00y0 *To whom reprint requests should be addressed. e-mail: PNAS is available online at http:yywww.pnas.org. [email protected]. 8417 Downloaded by guest on September 28, 2021 8418 Biochemistry: Lightstone et al. Proc. Natl. Acad. Sci. USA 94 (1997) Currently, it is computationally prohibitive to include an entire energy minimum, whereas the x-ray crystal structure is a enzyme in a quantum mechanical computation. In the present time-averaged structure. The calculated ground state is very study, the active site model consists of a crystallographic water similar to the gas-phase ion–molecule complex for the non- and the 14 amino acid residues (Glu-56, Asp-124, Trp-125, enzymatic reaction (Eq. 1) of DCE with acetate (16). It should Phe-128, Phe-172, Trp-175, Leu-179, Val-219, Phe-222, Pro- be noted that in 2, DCE is in a gauche-like conformation with 223, Val-226, Leu-262, Leu-263, and His-289; see Fig. 11) that a Cl-C-C-Cl dihedral angle of 74.2°, which also is similar to the surround the Asp-124 carboxylate anion nucleophile and the dihedral angle in the gas-phase ion–molecule complex (16). In 1,2-dichloroethane (DCE) substrate. Additional hydrogen at- the original x-ray crystallographic study, DCE was built into oms were included to satisfy all valences of the crystal structure the enzyme active site in a trans conformation during structure coordinates; the resulting system of partial amino acid struc- refinement, although the electron density for one of the tures and substrate contains 288 atoms. To retain the overall chlorines is not very strong (12–14). However, as indicated by structure of the system during the calculations, the peptide our previous ab initio calculations on the non-enzymatic backbone atoms were held fixed to their x-ray crystallographic reaction of AcO2 with DCE and the current calculations in the coordinates (2dhc) to compensate for the absence of the rest active site, DCE is probably in a gauche conformation or a of the enzyme. All side chain atoms and DCE were allowed to mixture of both trans and gauche when bound in the active site move. The PM3 (17) hamiltonian as implemented in GAUSSIAN of the enzyme. The gauche form is expected to have a stronger 94 (18) was used. PM3 was chosen based on the following interaction with the enzyme than the trans form because the observations. Our previous study (16) has demonstrated that former has a dipole. If DCE is in the trans form on approach the semiempirical PM3 method provides essentially the same to the carboxylate of Asp-124, there will be a large repulsion transition-state structure for the reaction of Eq. 1 as does ab between the negatively charged carboxylate group and the initio HFy6–311G(d) level of theory. The semiempirical PM3 chlorine on the adjacent carbon of DCE. This repulsion gets was chosen over AM1 (19) for comparison with ab initio stronger as DCE gets closer to the carboxylate; a simple calculations because AM1 tends to give bifurcated hydrogen conformational change (trans to gauche) alleviates this unfa- bonding geometries (20). Also, the large error associated with vorable interaction. Thus, the active form of DCE is the gauche AM1-calculated heat of formation of chloride ion (21) further conformation. limits its utility for our purpose. To determine the entire To locate a transition state, a stepwise procedure was reaction path of the substitution reaction, we calculated the followed. First, the gas-phase transition state was docked into structures of the following species: (1) the active site cavity the active site by superimposing the -CH2-COO- moiety of the modeled by the 14 residues and one water molecule; (2) the gas-phase transition state and the side chain carboxylate of active site containing 1,2-dichloroethane substrate (Fig. 2a); Asp-124. The transition state was optimized with the amino (3) the active site with the SN2 TS (Figs. 2b and 3); and (4) the acid side chains (including the crystallographic water) in a alkyl-enzyme ester product and leaving Cl2 that is held fixed state. Second, with the resulting transition state fixed, the between the NH groups of Trp-125 and Trp-175 (Fig. 2c). In amino acid side chains were optimized. Third, the transition all calculations, the Asp-124 is assumed to be ionized because state was optimized again with the optimized side chains fixed.
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