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Catalysis of a Stereospecific Bimolecular Amide Synthesis by an Antibody (Amide Bond Formation/Enantioselectivity/Monoclonal Antibody/Enzyme Mimicry) STEPHEN J

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Catalysis of a Stereospecific Bimolecular Amide Synthesis by an Antibody (Amide Bond Formation/Enantioselectivity/Monoclonal Antibody/Enzyme Mimicry) STEPHEN J Proc. Natl. Acad. Sci. USA Vol. 85, pp. 5355-5358, August 1988 Chemistry Catalysis of a stereospecific bimolecular amide synthesis by an antibody (amide bond formation/enantioselectivity/monoclonal antibody/enzyme mimicry) STEPHEN J. BENKOVIC*t, ANDREW D. NAPPER*, AND RICHARD A. LERNER§ *Department of Chemistry, The Pennsylvania State University, University Park, PA 16802; and §Department of Molecular Biology, Research Institute of Scripps Clinic, La Jolla, CA 92037 Contributed by Stephen J. Benkovic, April 25, 1988 ABSTRACT We report a nonhydrolytic bimolecular ami- 0 nolysis reaction catalyzed by an antibody. The stereospecific formation of an amide from racemic lactone plus an aromatic ko NHAc amine is described by a random equilibrium bireactant kinetic sequence. The observed turnover rate may be approximated from the measured difference between the binding of reactants and the transition state analog. Antibodies are the most diverse set of inducible binding proteins in biology consisting of about 1.0 x 108 unique specificities in the primary repertoire. During induction of an t I immune response, the processes of mutation and antigenic 0 OH 0 OH PhO , ,* NHAc selection of cells combine to yield new antibodies of ever- A.N~HAc 6- NJ increasing diversity and fine specificity. The binding energy 4 2 of antibodies induced to a single antigen expressed as a dissociation constant may span 10 orders of magnitude (K = FIG. 1. The transition states for the cyclization of ester 4 to 1.0 X 10 -41.0 X 10- mol-) (1). lactone 1, and ring opening of the latter by 1,4-phenylenediamine to Recently, chemists have begun to exploit the vast set of give amide 2, are mimicked by the cyclic phosphonate, 3. The antibody binding proteins to induce new catalysts. This has transition states shown are not necessarily those in the rate- been accomplished by designing haptens based on mecha- determining step of each reaction. nistic chemical principles so that the induced antibodies or relative to its binding of the transition state analog determine abzymes catalyze substrate transformations implicit in the the magnitude of the rate acceleration expected in the antigen design. To date, haptens that mimic the geometric absence of chemical catalysis. features ofthe transition states for hydrolytic acyl transfer (2- 5) and a concerted chemical reaction (Claisen rearrangement) (D. Hilvert, personal communication) have been used to MATERIALS AND METHODS induce catalytic antibodies. Furthermore, we have exploited Materials. Phosphonate 3 and ester 4 were synthesized as the inherent chirality of the antibody binding pocket to described (6). The concentration of stock solutions of 3 were catalyze the stereospecific cyclization of phenyl 6-acetami- 262.5 do-5-hydroxyhexanoate, 4, shown in Fig. 1 (6). determined by UV, using the value of E = 360 M -'-cm-1 The challenge now is to induce antibodies capable of for methyl phenyl phosphate (8). For solutions of 4 the catalyzing energetically more demanding chemical transfor- quantity of phenol released by complete cyclization at pH 7 mations such as amide bond hydrolysis or bimolecular was determined by using E271 = 860. The syntheses of synthetic reactions. We report here the catalysis by an lactone 1 and amide 2 are shown in Fig. 2. Separate syntheses abzyme of the stereospecific formation of an amide from a ofthe two enantiomers oflactone 1 were carried out as shown racemic lactone and an amine, specifically the reaction of in Fig. 3. The diastereomers of ester 5 were separated on 6-(acetamidomethyl)valerolactone, 1, with 1,4-phenylenedia- preparative TLC (Rf 0.28, 0.21; 5% methanol-CH2CI2). mine (Fig. 1). We reasoned that an antibody elicited to the The product Rf0.28 was obtained pure and was used directly; hapten, 2-phenoxy-2-oxo-6-(aminomethyl)-1,2-oxaphospho- the product Rf0.21 was subjected to three further preparative rinane, 3, which resembles the tetrahedral intermediate TLC separations to remove residual Rf 0.28 material. Each anticipated to form along either the aminolysis or cyclization diastereomer was separately stirred with 1 M NaOH for 40 hr route, might possess sufficient binding interactions to pro- at room temperature, after which the solution was acidified mote the bimolecular reaction. The reaction proceeds by a to pH 2 and extracted with CH2CI2 to remove a-methoxy- random kinetic sequence with respect to lactone and amine phenylacetic acid. Concentration of the aqueous residue, that involves separate binding sites in the antibody for the trituration with CH2Cl2, and silica column chromatography amine and lactone. The observed rate acceleration may be of the organic extract gave the desired lactone. Optical largely due to entropic factors without significant participa- rotations of the (- )- and (+ )-enantiomers were measured in tion by binding-site catalysts. A treatment, originating with tetrahydrofuran at a concentration of 10 and 1.0 mg-ml -, the development oftransition-state inhibitors (7), is applied to respectively. Production and purification of monoclonal illuminate how the distribution of binding energies of an antibody 24B11 have been described (6). antibody or abzyme for the participants in the reaction Antibody Assays. The concentration of catalytically active antibody and the Ki of phosphonate 3 were determined from a Henderson plot (9) of the inhibition of antibody 24B11- The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 5355 Downloaded by guest on September 27, 2021 5356 Chemistry: Benkovic et al. Proc. Natl. Acad. Sci. USA 85 (1988) catalyzed cyclization of phenyl 6-acetamido-5-hydroxyhex- H anoate, 4, by 3 (see Fig. 4). The reaction of 1,4-phen- MeO y.DU.NHAMc a .. a* the in )OHOH ylenediamine with lactone 1 was monitored by change H * UV absorbance at 308 nm (AE = 830) and by reversed-phase MooY._5jNHAc 1@O1*.N1% NHAc HPLC (Perkin-Elmer analytical C18 column, gradient of2.5- 0 0 7.5% CH3CN in H20 + 0.1% trifluoroacetic acid). The 0 0 appearance of amide product 2 was confirmed by collection )J' (R,R)-S ,I (R,S)-5 of the corresponding HPLC peak and positive identification MeO Ph MoO Ph by comparison of the mass spectrum to that of an authentic bJl Ltb H H sample. Antibody catalysis ofthe reaction was characterized HO NHAc by measuring initial rates from the linear UV absorbance HO Y--0i NHAc change corresponding to the first -4% of reaction. These O OH o OH data were corrected for the background reaction and used to 0 Lc obtain values of Km and kcat (Figs. 5 and 6). Antibody 24B11 0Ol was tested for enantioselectivity by comparison of the initial I NHAc rates of reaction of ( - )- and (+ )-1 with that of (± )-1 (Table I NHAc 2). H H (R)-(-)-l (S)-(+)-7 RESULTS [a]21=-70.2' [a]D2=+747 The syntheses of racemic lactone 1 and amide 2 are outlined in Fig. 2. Detailed procedures will be reported elsewhere. FIG. 3. Reagents and conditions: (a) (R)-( - )-a-methoxyphenyla- Separate syntheses of the two enantiomers of lactone 1 are cetic acid, dicyclohexylcarbodiimide, N,N-dimethylaminopyridine, outlined in Fig. 3. Enantiomeric purity was determined by pyridine, 22 hr; (b) 1 M NaOH, 40 hr, 25TC; (c) aqueous HCL. optical rotation and 1H NMR in the presence of a chiral shift catalytic activity was evident from following the first 4% of reagent, as described (6). Pending an x-ray crystal structure determination of the ester, 5, of the (-)-alcohol, tentative the reaction in the presence of 3.43 A.M antibody 24B11. This configuration assignments have been made on the basis ofthe activity was reduced to <20% in the presence of 6 AuM (0.88 observed specific rotations of 6-substituted valerolactones equivalent) phosphonate 3, and none was detectable with 24 (10-12). IuM 3, consistent with catalysis occurring in the binding site The Henderson plot (Fig. 4) of the inhibition of the for 3. Data obtained at a range of substrate concentrations antibody-catalyzed cyclization of ester 4 by phosphonate 3 were plotted as shown in Figs. 5 and 6, in accord with a rapid allowed determination of the concentration of active anti- equilibrium bireactant system. These graphs were used to body and the Ki of 3. From the intercept of Fig. 4, the obtain the values of Km and kcat shown in Table 1. The value concentration of active sites, 2[antibody] = 0.42 ,uM. Use of of Km for lactone 1 is based on the concentration of this value, rather than the total protein concentration, al- (- )-enantiomer in the racemic mixture. Comparison of the lowed revision ofthe previously reported (6) kcat value for the initial rates of reaction of 1,4-phenylenediamine with (-)-, cyclization to 2.36 minm '. The corresponding stock concen- (+ )-, and racemic (± )-lactone 1 (Table 2) shows the antibody tration of active abzyme was calculated as 13.6 tLM, and this catalysis to be enantioselective. Within experimental error, value was used to calculate [antibody] in all subsequent there is no measurable catalysis of the reaction of (+)-1. assays. Analysis of the gradients of the two lines (9) shows Furthermore, 1H NMR of 1 in the presence of a chiral shift that phosphonate 3 is a competitive inhibitor of the abzyme- reagent (see above) showed the active (-)-enantiomer to catalyzed cyclization, with Ki = 75 ± 3 nM. The Ki value is have the same configuration as that produced by antibody- less than that previously reported, which did not take into catalyzed cyclization of ester 4 (6). account the depletion of inhibitor by active antibody. The reaction of 1,4-phenylenediamine with lactone 1 gave 2.0 a measurable rate of decrease of UV absorbance at 308 nm due to consumption of 1,4-phenylenediamine.
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