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Choline Acetyltransferase and Acetylcholinesterase

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Choline Acetyltransferase and Acetylcholinesterase CHOLINE ACETYLTRANSFERASE AND ACETYLCHOLINESTERASE Haubrich, D. R. (1973), J. Neurochem. 21, 315. Ramasarma, J., and Wetter, L. R. (1957), Can. J. Bio- Liang, C., Segura, M., and Strickland, K. P. (1970), Can. chem. Physiol. 35, 853. J. Biocfiem. 48, 580. Sung, C., and Johnstone, R. M. (1967), Biochem. J. 105, Lowry, 0. H., Rosebrough, N. J., Farr, A. L., and Randall, 497. R. J. (1951),J. Biol. Chem. 193, 265. Weinhold, P. A., and Rethy, V. B. (1972), Biochim. Bio- McCaman, R. E. (1 962), J. Biol. Chem. 237, 672. phys. Acta 276, 143. McCaman, R. E., and Cook, K. (1966), J. Biol. Chem. 241, Wittenberg, J., and Kornberg, A. (1953), J. Biol. Chem. 3390. 202. 431. Choline Acetyltransferase and Acetylcholinesterase: Evidence for Essential Histidine Residues? Robert Roskoski, Jr. ABSTKACT: Choline acetyltransferase (EC 2.3.1.6) cata- dride also inactivates, and hydroxylamine reactivates, the lyzes the biosynthesis of acetylcholine according to the fol- partially purified electric eel acetylcholinesterase (EC lowing chemical equation: acetyl coenzyme A + choline + 3.1.1.7). High concentrations of acetylcholine substantially acetylcholine + coenzyme A. Ethoxyformic anhydride inac- protect against inactivation. The apparent pK a of the reac- tivates the enzyme prepared from bovine brain. Acetyl tive group is about 6.1. Inhibition by ethoxyformylation coenzyme A and coenzyme A, but not choline or acetylcho- which is reversed by hydroxylamine treatment provides evi- line, substantially protect against inactivation. The enzyme dence that histidine plays a role in the choline acetyltrans- is reactivated by hydroxylamine treatment. The apparent ferase and acetylcholinesterase reactions. pK, of the reactive group is about 6.5. Ethoxyformic anhy- Acety~cholineis an established neurotransmitter at the choline, possible alkylating reagents, on choline acetyltrans- vertebrate neuromuscular junction and a probable, but not ferase. These studies failed to implicate histidine; instead, proven, transmitter in the vertebrate central nervous system the enzyme was inhibited by bromoacetylation of the active (cJ Iverson, 1970). Choline acetyltransferase (EC 2.3.1.6) site sulfhydryl (Roskoski, 1974b). catalyzes the following reversible reaction: acetyl coenzyme In the present studies ethoxyformic anhydride inactiva- A + choline F= acetylcholine + coenzyme A. Several stud- tion and reversal by hydroxylamine treatment implicate his- ies support the notion of an essential enzymic sulfhydryl tidine in the choline acetyltransferase and acetylcholinester- group. For example, thiol reagents inhibit choline acetyl- ase (EC 3. I .1.7) enzyme reactions. Furthermore, both en- transferase from squid head ganglia (Reisberg, 1954), pri- zymes are inhibited by N- acetylimidazole and their activity mate placenta (Schuberth, 1966), torpedo (Morris, 1967), spontaneously returns to control values within 1 hr. These and mammalian brain (Potter et al., 1968; Chao and Wolf- results are consistent with the hypothesis that choline acet- gram, 1973; Roskoski, 1974a). Experiments with the bovine yltransferase and acetylcholinesterase are inhibited by brain transferase suggest that an active site -SH reacts with chemical modification of enzymic histidine residues. acetyl coenzyme A to form an acetyl-thioenzyme intermedi- ate (Roskoski, 1973, 1974a). This alleged thio ester inter- Experimental Section mediate, isolated by Sephadex gel filtration, further reacts Materials. Ethoxyformic anhydride and N- acetylimida- with choline to form acetylcholine. zole were purchased from Sigma Chemical Co. Electric eel Thio ester intermediates are also associated with the acetylcholinesterase (1058 units mg-I) was a product of glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12) Worthington Biochemical Corp. Acetylthiocholine chloride and papain (EC 3.4.4.10) reactions (Harris et a/., 1963; was purchased from Pfaltz and Bauer, Inc. Decamethonium Lowe and Williams, 1965). Crystallographic structural bromide was purchased from K and K Laboratories, Inc., analysis of the lobster muscle dehydrogenase (Buehner et and indoxyphenyl acetate, Calbiochem. al., 1973, 1974) and papain (Drenth et al., 1968) reveal a Methodology for Chemical Modification. For reaction histidine residue in close proximity to the active site -SH. with choline acetyltransferase, ethoxyformic anhydride, dis- The interaction of the imidazole with the sulfhydryl and solved in absolute ethanol, was added to give the specified with the substrates may be important in the catalytic mech- concentration of inhibitor. Ethoxyformic anhydride and N- anism of these enzymes. These findings prompted a study of acetylimidazole were dissolved in acetonitrile for the other the effects of bromoacetyl coenzyme A and bromoacetyl- experiments. These solutions were prepared immediately before use. A 1-4 solution of inhibitor was added to 100 @I ~~ ~-~~~~ ~ From the Department of Biochemistry, The University of Iowa, of enzyme solution to initiate the reaction unless specified lowa City, Iowa 52242. Received June 26, 1974. This work was sup- otherwise. Solvent alone was added to the control samples. ported by Grant NS-I 1310 of the U. s. Public Health Service. Acetylcholinesterase Assay. The spectrophotometric BIOCHEMISTRY, VOL. 13, NO. 25, 1974 5141 KOSKOSKI ~~~~ ~ TABLI I : Ethoxyformic Anhydride Inhibition of Choline TABLE 11: Effect of Substrates on Ethoxyformic Anhydride Acetyltransferase." Inhibition of Choline Acetyltransferaw." Enzyme Enzyme t n/ynie 4ctivity Actikity A, t IVI ty Concn (PM) (pmoli5 min) Concn (PM) (pmol/5 min) Addition Contn (".r; Control) 0 94 2 50 7s None ?(I 10 64 1 100 38 Acetyl 15 pv 0 2 25 17 9 1000 0 coenzyme A Coenzyme A 15 phl 62 "The enzyme extract (20 pg of protein) was incubated 5 Acetylcholine 2 mv '8 min at 37" in buffer C (SO mM potassium phosphate- 100 mv Choline 2, 10 mM 31 KCI-0.1 mM EDTA (pH 7.4)) with the specified concentra- -_ -- ~ tion of reagent in 100 pl. Then 10-111 aliquots were assayed The experiment was carried out a\ described in Table I for choline acetyltransferase activity as previously described except that the enzyme was preincubateti 5 min at 37" with (Roskoski, 1973) the specified iub\trate prior to the addition of ethoxyformic anhydride (25 pihi final) The control kalue was 88 pmol 5 min The apparent K, values were previously reported acetyl coenzyme A, 15 choline, 0 75 mv. coenzyme A, 20-200 procedure of Ellman and coworkers (1961) was used. Ali- p~: p~;acetylcholine 1-5 mv (Roskosbi, 1974a) quots of enzyme (to 20 PI) were added to 300 pl of 0.1 M potassium phosphate (pH 7.0), 2 mM acetylthiocholine, and 0.25 mM 5,5'-dithiobis(2-nitrobenzoic acid). The absorb- ance changes at 412 nm (1-cm path length) were followed on a Beckman 25 spectrophotometer. With indoxylacetate 98%. These results are consistent with the hypothesis that and p- nitrophenyl acetate as substrates, assays were carried enzyme inhibition is associated with ethoxyformylation of out using the methodology of O'Brien (1969) except that an enzymic histidine residue (Melchoir and Fahrney, 1970; the volumes were scaled down to 300 pl. Esterase assays Burstein et ul., 1974). were performed at ambient temperature. Determination of the pK, of the Reactive Kesidue. The Preparation of the bovine brain choline acetyltransferase pH dependence of the ethoxyformic anhydride inhibition of and the radiochemical enzyme assay were described pre- the choline acetyltransferase was measured after a 5-min viously (Roskoski, 1973). Sources of other materials are incubation. The apparent first-order rate constants (K~,,,,,) previously documented (Roskoski, 1973, 1974a). were calculated using the methodolog) of Burstcin and co. workers (1974) (Table 111). A-pK, of 6.5 f 0.3 was calcu- lated from the slope of such a plot using the data given in Results Table IV. The experiment was performed in quadruplicate. General Characteristics of Ethoxyformic Anhydride In- Ethoxyformic Anhydride Inhibition of ..lcet,ylcholitiest- hibition of Choline Acetyltransferase. Ethoxy formic anhy- erase. Because of the evidence supporting the contention of dride proved to be a potent inhibitor of transferase activity essential histidine residues in acetylcholinestcrase ((j: (Table I). A 50 /IM concentration inhibits activity 92% Cohen and Oosterbaan, l963), ethoxyformic anhydride in- under standard experimental conditions (37'. 5 min, pH activation of the electric eel enzyme mas tested. Incubation 7.4). Although the reaction conditions differ. concentra- with 0.35 m~ ethoxyformic anhydride for 5 min at 23' (pli tions used for the ethoxyformylation of creatine kinase 7.0) inhibits enzyme activity 50%. Similar results are ob- (Pradel and Kassab, 1968), pepsin, and pancreatic RNase served using the neutral substrates indoxyl acetate and p- (Melchoir and Fahrney, 1970) are three to five orders of nitrophenyl acetate. Inactivation is proportional to reagent magnitude greater than those reported here. The inactiva- concentration, and good pseudo-first-order kinetics obtain tion is proportional to the reagent concentration and cxhib- during the 5-min reaction, its good pseudo-first-order kinetics during the 5-min reac- The rate of acetylcholinesterase inhibition was measured tion. Since the inhibitor hydrolyzes with a t 112 of aborit 27 in the presence of several substrates and inhibitors. Coni- min at pH 7 (Melchoir and Fahrney, 1970), these kinetics pounds which bind to the substrate anionic site (Froede and do not obtain during long incubations. Wilson. I971 including
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