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An Unexpected Event When Chymotrypsin Performs Its Physiological Role Ivan G. Darvey Department of Biochemistry, The University of Sydney, Sydney, NSW 2006, Australia;
[email protected] When students are taught about the general properties of derivatives of carboxylic acids in introductory organic chemistry courses, they are probably told that the reactivity of derivatives of carboxylic acids decreases in the order acid chlorides > acid anhydrides > esters > amides, and thus that, for reactions generally carried out in organic chemistry laboratories, amides can be synthesized from esters, but the synthesis of esters from amides is difficult (1–4). It seems a pity that authors of introductory textbooks of biochemistry (5–10), and probably therefore biochemistry teachers, do not refer to these general properties of carboxylic acid derivatives when discussing the mechanism of the chymotrypsin-catalyzed hydrolysis of peptide (substituted amide) bonds. If reference were made to these properties, then students could be told that one of the events that occur during the chymotrypsincatalyzed hydrolysis of peptide bonds is an example of an exception to the rule of thumb that amides can’t readily be converted to esters. In forming an acyl–enzyme intermediate, chymotrypsin converts an unreactive stable substituted amide present in the substrate molecule to a more reactive ester intermediate, in which the acyl group of the substrate is covalently bound to a serine residue at the active site of the enzyme. Once formed, this more reactive ester intermediate present at the enzyme’s active site undergoes hydrolysis. Thus, one of the major steps performed when chymotrypsin carries out its main perceived “physiological role”, namely, the hydrolysis of certain peptide bonds in proteins in the small intestine, is the unexpected formation of an ester from a substituted amide. If biochemistry teachers reminded students about the usual order of reactivity of carboxylic acid derivatives and then commented on the ability of chymotrypsin to catalyze the formation of an ester from an amide, it would emphasize further the remarkable role that chymotrypsin plays as a
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catalyst in carrying out its physiological action. Organic chemistry teachers could use chymotrypsin as an example of a situation where the general rule of thumb relating to the reactivity of derivatives of carboxylic acids does not apply. Acknowledgments I wish to thank Philip Kuchel and Max Crossley for reading drafts of this communication and for providing critical comments and advice. Literature Cited 1. Brown, W. H. Introduction to Organic Chemistry, 4th ed.; Brooks/Cole: Pacific Grove, CA, 1988; pp 360, 361. 2. Carey, F. A. Organic Chemistry, 2nd ed.; McGraw-Hill: New York, 1992; pp 807–810. 3. McMurry, J. Organic Chemistry, 4th ed.; Brooks/Cole: Pacific Grove, CA, 1995; pp 808, 809. 4. Solomons, T. W. G. Organic Chemistry, 5th ed.; Wiley: New York, 1992; p 774. 5. Garrett, R. H.; Grisham, C. M. Biochemistry; Saunders: Fort Worth, 1995; pp 436–441. 6. Lehninger, A. L.; Nelson, D. L.; Cox, M. M. Principles of Biochemistry, 2nd ed.; Worth: New York, 1993; pp 223–227. 7. Mathews, C. K.; van Holde, K. E. Biochemistry, 2nd ed.; Benjamin/Cummings: Menlo Park, CA, 1996; pp 372–375. 8. Moran, L. A.; Scrimgeour, K. G.; Horton, H. R.; Ochs, R. S.; Rawn, J. D. Biochemistry, 2nd ed.; Neil Patterson/Prentice Hall: Englewood Cliffs, NJ, 1994; pp 6.25–6.32. 9. Stryer, L. Biochemistry, 4th ed.; Freeman: New York, 1995; pp 222–227. 10. Voet, D.; Voet, J. G. Biochemistry, 2nd ed.; Wiley: New York, 1995; pp 389–400.
Journal of Chemical Education • Vol. 77 No. 3 March 2000 • JChemEd.chem.wisc.edu
