Ester hydrolysis pathway

Fig. 7.1. a) Specific acid catalysis (proton catalysis) with acyl cleavage in ester hydrolysis. Pathway a is the common mechanism involving a tetrahedral intermediate. Pathway b is SN1 mechanism observed in the presence of concentrated inorganic acids. Not shown here is a mechanism of alkyl cleavage, which can also be observed in the presence of concentrated inorganic acids, b) Schematic mechanism of general acid catalysis in ester hydrolysis. 

Hydrolysis. Esters are cleaved (hydroly2ed) into an acid and an alcohol through the action of water. This hydrolysis is cataly2ed by acids or bases. The mechanistic aspects of ester hydrolysis have received considerable attention and have been reviewed (16). For most esters only two reaction pathways are important. Both mechanisms involve a tetrahedral intermediate and addition-elimination reactions i7i7... 

Acid-catalyzed ester hydrolysis can occur by more than one mechanism, depending on the structure of the ester. The usual pathway, however, is just the reverse of a Fischer esterification reaction (Section 21.3). The ester is first activated toward nucleophilic attack by protonation of the carboxyl oxygen atom, and nucleophilic addition of water then occurs. Transfer of a proton and elimination of alcohol yields the carboxylic acid (Figure 21.8). Because this hydrolysis reaction is the reverse of a Fischer esterification reaction, Figure 21.8 is the reverse of Figure 21.4. 

The lipase-catalyzed fatty acid ester hydrolysis and the lipoxygenation of free polyunsaturated fatty acids are involved in the same lipid degradation pathway. They are respectively the first and second reaction in the lipoxygenase pathway (Fig. 3) [87-91]. The pathway produces volatile products of considerable importance in food technology including Cg[92, 93] or Cg- 94—96 aldehydes and alcohols from polyunsaturated fatty... 

The pronounced proclivity of phosphoric monoester monoanions to eliminate POf is not always recognizable from the characteristic pH profile of Fig. 1. The hydrolysis rate maximum at pH w 4 may be masked by a faster reaction of the neutral phosphoric ester, as in the case of a-D-glucose 1-phosphate63) or on hydrolysis of monobenzyl phosphate 64). In the latter case, the known ability of benzyl esters to undergo SN1 and SN2 reactions permits fast hydrolysis of the neutral ester with C/O bond breakage. The fact that the monoanion 107 of the monobenzyl ester is hydrolyzed some 40 times faster than the monoanion 108 of the dibenzyl ester at the same pH again evidences the special hydrolysis pathway of 107, rationalized by means of the metaphosphate hypothesis. 

Considering first the simpler of the two cases, the straight line for the methyl esters (34a) which has a p value of -3-25. From this p value it is apparent that this reaction cannot be proceeding via the normal (Aac2) pathway (p. 241) for acid-catalysed ester hydrolysis which, as we know (reaction 6, p. 364), has a p value of +0-03. That value refers, however, to hydrolysis being carried out with dilute sulphuric acid, while here 99-9% sulphuric acid is being used one... 

We have, however, already seen an alternative acid hydrolysis pathway (Aac1, p. 242) in which a water molecule is not involved in the slow, rate-limiting step. In addition, this step is one in which considerable +ve charge is developed at the reaction centre as the protonated ester (35a) is converted into the acyl cation intermediate (36a) a necessary requirement for a reaction with a large -ve (-3-25) p value ... 

Scheme 6 depicts three possible hydrolysis mechanisms.140 The first (pathway (i)) is normal acid-catalysed ester hydrolysis in which attack of solvent (H20) upon the protonated intermediate is rate determining. The second (pathway (ii)) is the... 

Fig. 3.1. General scheme for chemical hydrolysis of carboxylic acid esters and amides. Pathway a Proton (general acid) catalyzed hydrolysis. Pathway b HO (general base) catalyzed...

The term acid catalysis is often taken to mean proton catalysis ( specific acid catalysis ) in contrast to general acid catalysis. In this sense, acid-catalyzed hydrolysis begins with protonation of the carbonyl O-atom, which renders the carbonyl C-atom more susceptible to nucleophilic attack. The reaction continues as depicted in Fig. 7. l.a (Pathway a) with hydration of the car-bonium ion to form a tetrahedral intermediate. This is followed by acyl cleavage (heterolytic cleavage of the acyl-0 bond). Pathway b presents an mechanism that can be observed in the presence of concentrated inorganic acids, but which appears irrelevant to hydrolysis under physiological conditions. The same is true for another mechanism of alkyl cleavage not shown in Fig. 7.Fa. All mechanisms of proton-catalyzed ester hydrolysis are reversible. 

N-Me group is partly followed by A-demelhylalion, and the oxidation products can also undergo ester hydrolysis. As a result, several metabolic pathways convert bambuterol to terbutaline, and both plasma and liver microsomal enzymes may be involved. 

Metabolism - The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 is not expected to contribute significantly to the elimination of trospium. 

Parenthetically, it should be noted that there is evidence for the accumulation of an acylenzyme (i.e., a mixed anhydride with Glu-270) in the carboxypeptidase A-catalyzed hydrolysis of esters at low temperature, but this evidence does not include confirmation by chemical trapping experiments (Makinen et al, 1979 Kuo and Makinen, 1982 Suh et al., 1985). This would imply a nucleophilic, rather than promoted-water, pathway for ester hydrolysis. Sander and Witzel (1985) provided the only... 

Ester hydrolysis, alcoholysis, and aminolysis may be regarded as substitution reactions (via addition-elimination pathways). The activation of (methylthio)methyl esters by S-methylation [51] is an example demonstrating the usefulness of polarity alternation accentuation. 

Surface-catalyzed dark and photoassisted phosphate ester hydrolysis (P—O bond rupture) in aqueous suspensions of TiO2 has been proposed [6,7,41]. A number of products indicative of radical cationic pathways have been reported in the TiO2 photocatalysis of benzyl phosphonic acid [44]. 

In fact this pathway cannot be a great deal more favourable than the normal ester hydrolysis (Aac2) mechanism since this appears in the case of methoxy-methyl formate80, is dominant in the hydrolysis of /3-chloroethoxy methyl acetate81, CICH2CH2OCH2OCOCH3, and is apparently the sole important mechanism for the hydrolysis of methylene diacetate, CH ,COO CH2-OCOCH,82. 

In cases of promiscuous activity, one species in the pathway often acts as a common intermediate for both mechanisms leading to different activities. An enam-ine between PLP and the substrate branches off into a decarboxylation or a transamination, a TPP-bound intermediate can react either to decarboxylation or to carboligation, and the triad Ser-His-Asp in hydroxynitrile lyase is responsible for both the main function, oxynitrilation, and the subordinate function, ester hydrolysis. It can be assumed that many more promiscuous functionalities will be discovered in the coming years. 

The lipase-catalysed hydrolysis of methyl 2-fluoro-2-arylpropionates was proposed to proceed via a mechanism whereby, after ester hydrolysis, the enzyme facilitates the elimination of fluoride ion with the formation of a carbocation stabilized by the adjacent C02 group.230 Determination of the crystal structure of human sialidase Neu2, an enzyme that catalyses the hydrolysis of sialic acids, reveals a tyrosine residue that is positioned in the active site to stabilize the carbocation proposed as an intermediate in the hydrolysis.231 ll-Fluoro-all-frans-retinol is found to undergo isomerization to its 11 -cis form in the presence of visual cycle enzymes, in contrast to a previous study where no isomerization was reported.232 The result of the prior study was taken as evidence for a carbonium ion pathway in the isomerization. Although the authors of the present study do not rule out such a mechanism, they suggest that the isomerization mechanism remains unknown. Data obtained in a study of the oxidation of... 

This was nicely outlined with the observed unusually high enantiopurity of the dehalogenation consecutive product ethyl L-3-hydroxybutyrate (l-4 Pathways II, III). Ester hydrolysis product 16 acts as an inhibitor of D-directing /3-ketoacyl reductase of the fatty acid synthase (FAS) complex (EC 1.1.1.100) [69, 70], whereupon the fraction of l-4 increased from 97% ee to >99.5% ee. 

Gee and Langstrom synthesized255 1 -labelled a-methyl l-tyrosine via alkylation of a malonate derivative, enzymatic ester hydrolysis, conversion of carboxylic moiety to isocyanate followed by hydrolysis of the ester and isocyanate groups. Labelling of the a-posi-tion of the a-methyl L-tyrosine with 14C and UC, has been achieved also according to the pathway shown in equation 125256. 

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