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Chapter 49 Suggested solutions for Chapter 49 469 The second compound is a nerve gas style of phosphorus compound that interferes with acetyl choline metabolism and could destroy nerve function. Thiols are excellent nucleophiles for phosphorus and glutathione forms a thiol ester with the phosphate. The thiol is a better nucleophile than the OH group on the enzyme and, in any case, gets there first. Et0 Et0 0 0 P CI CI SG Et0 Et0 SG Et0 HS-G The third compound, an exo-methylene lactone, is carcinogenic and might react by conjugate addition with proteins and nucleic acids if glutathione does not react more quickly. Fortunately, thiols are excellent at conjugate addition. SG SG HS H 0 0 0 0 0 In all these cases, detoxification by glutathione uses the very reaction that makes the toxin dangerous in the first place. If glutathione is not around in sufficient quantity, or if an enzyme is just too quick at reaction with the toxin, glutathione is not good enough to prevent damage. Problem 8 Alanine can be resolved by the following method, using a pig kidney acylase. Draw a mechanism for the acylation step. Which isomer of alanine acylates faster? In the enzyme-catalysed reaction, which isomer of the amide hydrolyses faster? In the separation, why is the mixture heated in acid solution, and what is filtered off? How does the separation of the free alanine by dissolution in ethanol work? If the acylation is carried out carelessly, particularly if the heating is too long or too strong, a 0 pig kidney Ac2O acylase HN HN CO₂H AcOH pH 8, 37 °C racemic alanine CO₂H four hours CO₂H 0 NH₂ 1. HOAc, heat HN 2. filter hot 1. EtOH, heat NHAc NH₂ solid material 3. concentrate 2. filter CO₂H CO₂H CO₂H 4. cool and filter in solution crystallizes by-product may form that is not hydrolysed by the enzyme. How does this happen? NH₂ AcOH N racemic alanine 0 overheating Purpose of the problem Rehearsal of some basic amino acid and enzyme chemistry plus revision of stereochemistry (Chapter 16) and asymmetric synthesis (Chapter 45). Suggested solution Do you feel that was a catch The acylation takes place by the normal mechanism for the formation of amides from anhydrides, question? It was in a way but it is that is, by nucleophilic attack on the carbonyl group and loss of the most stable anion (acetate) from very important that you cling on to the fact that the chemistry of the tetrahedral intermediate. The two isomers of alanine are enantiomers. Enantiomers must react at enantiomers is the same except identical rates with an achiral reagent like acetic anhydride. with chiral reagents.