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NM:R Evidence for the Participation of a Low-Barrier Hydrogen Bond in The Proc. Natl. Acad. Sci. USA Vol. 93, pp. 8220-8224, August 1996 Biochemistry NM:R evidence for the participation of a low-barrier hydrogen bond in the mechanism of A5-3-ketosteroid isomerase (proton transfer/catalysis/fractionation factor/ligand binding/enolization) QINJIAN ZHAOab, CHITRANANDA ABEYGUNAWARDANAa, PAUL TALALAYb, AND ALBERT S. MILDVANac Department of aBiological Chemistry and bPharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 Contributed by Paul Talalay, May 15, 1996 ABSTRACT A5-3-Ketosteroid isomerase (EC 5.3.3.1) pro- the mechanism of isomerase would resolve a perplexing ques- motes an allylic rearrangement involving intramolecular pro- tion concerning the large and unfavorable difference in pKa ton transfer via a dienolic intermediate. This enzyme en- values between the 3-carbonyl group of the substrate (pKa = hances the catalytic rate by a factor of 1010. Two residues, -7) and that of the general acid, Tyr-14 (pKa = 11.6) (7). The Tyr-14, the general acid that polarizes the steroid 3-carbonyl concerted enolization is facilitated by stabilization of the group and facilitates enolization, and Asp-38 the general base incipient dienolate through unusually strong hydrogen bond- that abstracts and transfers the 4(3-proton to the 6j3-position, ing with Tyr-14. The strength of this hydrogen bond (H-bond) contribute 104.7 and 105-6 to the rate increase, respectively. A is at least 7.6 kcal/mol, as estimated from the relative k0ff major mechanistic enigma is the huge disparity between the values of the intermediate dienolate from the Y14F mutant pK, values of the catalytic groups and their targets. Upon which lacks Tyr-14 (40 s-1), and the D38N mutant which binding of an analog of the dienolate intermediate to isomer- retains Tyr-14 (s9.4 x 10-5 s-1) (5). The rate constant (koff) ase, proton NMR detects a highly deshielded resonance at cannot be measured on the wild-type enzyme because of rapid 18.15 ppm in proximity to aromatic protons, and with a 3-fold product formation. This strong H-bond has two characteristics preference for protium over deuterium (fractionation factor, of an LBHB: approximately matched pKa values of the donor 4) = 0.34), consistent with formation of a short, strong and acceptor, and exclusion of bulk solvent (6, 9). Thus, the (low-barrier) hydrogen bond to Tyr-14. The strength of this PKa of Tyr-14 in the free enzyme is 11.6 (7), whereas the pKa hydrogen bond is estimated to be at least 7.1 kcal/mol. This value of the dienolic intermediate is 10 in water (12) and is bond is relatively inaccessible to bulk solvent and is pH likely to be higher on the enzyme. The local dielectric constant insensitive. Low-barrier hydrogen bonding of Tyr-14 to the near Tyr-14 in the free enzyme is =18, as estimated by three intermediate, in conjunction with the previously demon- independent methods (7), and probably further decreases in strated tunneling contribution to the proton transfer by the enzyme-steroid complex, suggesting exclusion of solvent Asp-38, provide a plausible and quantitative explanation for from the active site. The present studies provide direct NMR the high catalytic power of this isomerase. evidence for the existence of an LBHB between Tyr-14 and the dienolic intermediate of isomerase. A5-3-Ketosteroid isomerase (EC 5.3.3.1) from Pseudomonas testosteroni is a homodimeric protein containing 125 amino MATERIALS AND METHODS acids in each subunit. This enzyme converts A5-3-ketosteroids to A4-3-ketosteroids via a dienolic intermediate with diffusion- Materials. 1713-Dihydroequilenin (1,3,5(10),6,8-estrapen- controlled efficiency. Concerted general acid-base catalysis by taene-3,17,B-diol) (DHE), estradiol 17f3-hemisuccinate, 4-flu- two amino acid residues is essential for achieving this catalytic oroestradiol, and 19-nortestosterone hemisuccinate (obtained perfection (1,2). In the rate-limiting substrate enolization step, from Steraloids, Wilton, NH) all showed a single spot on TLC Asp-38 removes the 413-proton of the steroid while Tyr-14 and were used without further purification. Ammonium sul- stabilizes the developing dienolate intermediate. In the sub- fate, buffer salts, sodium chloride, deuterium oxide, and sequent reketonization step, Asp-38 delivers the conserved perdeuterated dimethyl sulfoxide (DMSO-d6) were from proton to the 613-position, and the interaction of the steroid Sigma. Sodium 4,5-dihydroxynaphthalene-2,7-disulfonate was with Tyr-14 weakens (see Fig. 1). The origin of the large from Aldrich. catalytic rate enhancement (-1010) of the isomerase has been Sample Preparation. The D38N, Y55F/Y88F, and Y14F/ a continuing and perplexing issue (3). Here, we report direct Y88F mutant isomerase enzymes were prepared, and their NMR spectral evidence for the existence of a short, strong or concentrations were determined as reported (1, 7, 13-15). low-barrier hydrogen bond (LBHB) between the acid catalyst, NMR samples were prepared in 10 mM sodium phosphate, 20 Tyr-14, and an analog of the dienolate intermediate in the mM sodium chloride, and 9% (vol/vol) DMSO-d6 at indicated reaction mechanism of A5-3-ketosteroid isomerase. We sug- pH values. DMSO was added to the system to stabilize the gest that the LBHB is a significant contributor to the inter- isomerase in aqueous solution and to permit lowering of the mediate stabilization and catalytic power of the enzyme. temperature to below 0°C. Its presence does not significantly Nuclear Overhauser effect (NOE) studies have shown that affect the activity or structure of isomerase (14). pH values Tyr-14 closely approaches the A ring of a bound 3-ketosteroid were measured at 22°C in the presence of 9% (vol/vol) (4), and kinetic studies of the Y14F mutant indicate that DMSO-d6. Tyr-14 contributes a factor of -1047 to the total catalytic power (1010) of the isomerase (3,5). Although the existence of Abbreviations: D38N, mutant isomerase in which Asp-38 is replaced an LBHB between Tyr-14 and the dienolate intermediate on by asparagine; DHE, 173-dihydroequilenin (1,3,5(10),6,8-estrapen- the isomerase has been suspected (6-11), direct observation of taene-3,1713-diol); DMSO-d6, perdeuterated dimethyl sulfoxide; H- this LBHB has been elusive. The participation of an LBHB in bond, hydrogen bond; isomerase, A5-3-ketosteroid isomerase (EC 5.3.3.1); LBHB, low-barrier hydrogen bond; NOE, nuclear Overhauser effect; Y14F/Y88F, mutant isomerase in which Tyr-14 and Tyr-88 are The publication costs of this article were defrayed in part by page charge replaced by phenylalanine; Y55F/Y88F, mutant isomerase in which payment. This article must therefore be hereby marked "advertisement" in Tyr-55 and Tyr-88 are replaced by phenylalanine. accordance with 18 U.S.C. §1734 solely to indicate this fact. cTo whom reprint requests should be addressed. 8220 Downloaded by guest on October 1, 2021 Biochemistry: Zhao et al. Proc. Natl. Acad. Sci. USA 93 (1996) 8221 Conditions for NMR spectroscopy of enzymes and enzyme- hydroxyl proton in a random coil (21). The extraordinarily steroid complexes are given in the figure legends. The CE and strong deshielding of this proton suggests that it is located C8 proton resonance of Tyr-14 (6.78 and 6.88 ppm, respec- almost symmetrically between two oxygen atoms. tively) were assigned previously (4, 14). The spectra of ionized The Y55F/Y88F mutant of isomerase shows a kcat/Km value DHE were recorded in 0.1 M NaOH in presence of 9% of -80% of the wild-type enzyme and contains Tyr-14 as the (vol/vol) DMSO-d6 at -3.3°C. The resonances of aromatic sole tyrosine residue. When this enzyme was complexed with protons in the A and B rings of the steroid were assigned based a more soluble intermediate analog, estradiol 17,B-hemisucci- on one-dimensional proton NOEs. nate, a low field resonance (18.15 ppm) was also observed, Determination of the Fractionation Factor. The general whereas this peak was absent in the complex between this procedure of Loh and Markley (16) was used. Six samples with enzyme and 19-nortestosterone hemisuccinate (data not varying amounts of H20/D20 (12.4, 25.3, 40.3, 55.2, 70.1, and shown). Furthermore, this peak and the 11.60-ppm peak were 83.0% mole fraction H20) were prepared from 110 ,ul of a not observed under the same conditions in the absence of stock solution containing 1.5 mM D38N mutant in 10 mM Tyr-14 (i.e., with the Y14F/Y88F double mutant complexed sodium phosphate, measured pH 7.2, in D20 (4.2% H20), by with estradiol 17,B-hemisuccinate). Two further observations parallel dilutions (to 600 pl) with H20/D20 mixtures of known are consistent with an LBHB. First, replacement of DHE (pKa ratios. DHE was added to each solution (134 mM solution in = 9.0) on the D38N mutant with 4-fluoroestradiol (pKa = 7.4), DMSO-d6) to a final concentration of 0.45 mM. All solutions which increases the difference in pKa from that of Tyr-14, contained 9.0% (vol/vol) DMSO-d6. The mixtures were incu- decreases the deshielding effect, shifting the resonance from bated at 4°C for 30 min before NMR experiments. No changes 18.15 ppm to 16.41 ppm at -3.3°C. Second, this site strongly in intensities of the resonance at 18.15 ppm were seen in prefers protium to deuterium (22). Thus, a plot of the intensity representative samples after 1 week at 4°C. of the 18.15 ppm resonance as a function of the mole fraction of H20 (16) (Fig.
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