Nucleophilic acyl substitution reactions biological

Ester hydrolysis is common in biological chemistry, particularly in the digestion of dietary fats and oils. We ll save a complete discussion of the mechanistic details of fat hydrolysis until Section 29.2 but will note for now that the reaction is catalyzed by various lipase enzymes and involves two sequential nucleophilic acyl substitution reactions. The first is a trcinsesterificatiori reaction in which an alcohol gioup on the lipase adds to an ester linkage in the tat molecule to give a tetrahedral intermediate that expels alcohol and forms an acyl... 

Thus, penicillin and other p-lactam antibiotics are biologically active precisely because they undergo a nucleophilic acyl substitution reaction with an important bacterial enzyme. 

The carbon-sulfur bond of a thioester is rather long—typically on the order of 180 pm—and delocalization of the sulfur lone-pair electrons into the rr orbital of the carbonyl group is not as effective as in esters. Nucleophilic acyl substitution reactions of thioesters occur faster than those of simple esters. A number of important biological processes involve thioesters several of these are described in Chapter 26. 

Activation of Carboxylate Ions for Nucleophilic Acyl Substitution Reactions in Biological Systems... 

Because these mixed anhydrides are negatively charged, they are not readily approached by nucleophiles. Thus, they are used only in enzyme-catalyzed reactions. One of the functions of enzymes that catalyze biological nucleophilic acyl substitution reactions is to neutralize the negative charges of the mixed anhydride (Section 27.5). Another function of the enzyme is to exclude water from the site where the reaction takes place. Otherwise hydrolysis of the mixed anhydride would compete with the desired nucleophilic acyl substitution reaction. 

Esters can also be synthesized by a nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol. Fischer and Speier discovered in 1895 that esters result simply from heating a carboxylic acid in alcohol solu-Biological tion containing a small amount of strong acid catalyst. Yields are good in this onnection Fischer esterification reaction, but the need to use excess alcohol as solvent limits the method to the synthesis of methyl, ethyl, and propyl esters. 

Nucleophilic acyl substitution reactions take place in living organisms just as they take place in the chemical laboratory. The same principles apply in both cases. Nature, however, often uses a thiol ester, RCOSR, as the ackk Biological t derivative because it is intermediate in reactivity between an acid anhy-... 

Carboxylic acid derivatives are among the most widespread of all molecules, both in laboratory chemistry and in biological pathways. Thus, a study of them and their primary reaction—nucleophilic acyl substitution—is fundamental to understanding organic chemistry. We ll begin this chapter by first learning about carboxylic acid derivatives, and then we ll explore the chemistry of acyl substitution reactions. 

Amide hydrolysis is common in biological chemistry. Just as the hydrolysis of esters is the initial step in the digestion of dietary fats, the hydrolysis of amides is the initial step in the digestion of dietary proteins. The reaction is catalyzed by protease enzymes and occurs by a mechanism almost identical to that we just saw for fat hydrolysis. That is, an initial nucleophilic acyl substitution of an alcohol group in the enzyme on an amide linkage in the protein gives an acyl enzyme intermediate that then undergoes hydrolysis. 

Biochemistry is carbonyl chemistiy. Almost all metabolic pathways used by living organisms involve one or more of the four fundamental carbonvl-group reactions we ve seen in Chapters 19 through 23. The digestion and metabolic breakdown of all the major classes of food molecules—fats, carbohydrates, and proteins—take place by nucleophilic addition reactions, nucleophilic acyl substitutions, a substitutions, and carbonyl condensations. Similarly, hormones and other crucial biological molecules are built up from smaller precursors by these same carbonyl-group reactions. 

Nucleophilic acyl substitution is a common reaction in biological systems. These acylation reactions are called acyl transfer reactions because they result in the transfer of an acyl group from one atom to another (from Z to Nu in this case). 

The hydrolysis of a carboxylic acid derivative is but one example of a nucleophilic acyl substitution. Nucleophilic acyl substitutions connect the various classes of carboxylic acid derivatives, with a reaction of one class often serving as preparation of another. These reactions provide the basis for a large number of functional group transformations both in synthetic organic chemistry and in biological chemistry. 

This pattern of increased reactivity resulting from carbonyl group protonation has been seen before in nucleophilic additions to aldehydes and ketones (Section 17.6) and in the mechanism of the acid-catalyzed esterification of carboxylic acids (Section 19.14). Many biological reactions involve nucleophilic acyl substitution and are catalyzed by enzymes that act by donating a proton to the carbonyl oxygen, the leaving group, or both. 

Thioesters and oxoesters are similar in their rates of nucleophilic acyl substitution, except with amine nucleophiles for which thioesters are much more reactive. Many biological reactions involve nucleophilic acyl substitutions referred to as acyl transfer reactions. The thioester acetyl coenzyme A is an acetyl group donor to alcohols, amines, and assorted other biological nucleophiles. 

Polyesters, nylon, and many biological molecules share a common aspect of bond formation during their synthesis. This process is called acyl substitution, and it involves creation of a bond by nucleophilic addition and elimination at a carbonyl group. Acyl substitution reactions occur every moment of every day in our bodies as we biosynthesize proteins, fats, precursors to steroids, and other molecules and as we degrade food molecules to provide energy and biosynthetic raw materials. Acyl substitution reactions are used virtually nonstop in industry as well. Approximately 3 billion pounds of nylon and 4 billion pounds of polyester fibers are made by acyl substitution reactions every year. The molecular graphic above is a portion of a nylon 6,6 polymer. 

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