Thioester group

Reduction of the thioester group by 2 equivalents of NADPH gives (ft)-mevalonate, a dihydroxy acid. 

The overall result is a "hydrolysis" of the thioester group without involvement of water. 

From the results of the fluorescence spectroscopic study it is concluded that excitation energy at the lowest excited state of a PDA derivative having a thioester moiety is localized at the thioester group intra- or inter-molecular energy transfer from the conjugated system of the PDA to the thioester moiety must have occurred in the crystalline state to afford a photostable crystal (Hasegawa et al., unpublished data). 

The subsequent conversion of HMG-CoA into MVA involves a two-step reduction of the thioester group to a primary alcohol (see Section 7.11), and provides an essentially irreversible and rate-limiting transformation. Drug-mediated inhibition of this enzyme, HMG-CoA reductase (HMGR), can be used to regulate the biosynthesis of the steroid cholesterol. High levels of blood cholesterol are known to contribute to the incidence of coronary heart disease and heart attacks. 

Proteolytic cleavage of factor C3 provides two components with different effects. The reaction exposes a highly reactive thioester group in C3b, which reacts with hydroxyl or amino groups. This allows C3b to bind covalently to molecules on the bacterial surface (opsonization, right). In addition, C3b initiates a chain of reactions leading to the formation of the membrane attack complex (see below). Together with C4a and C5a (see below), the smaller product C3a promotes the inflammatory reaction and has chemotactic effects. 

The presence of the fluoromethyl thioester group in fluticasone (30-4) requires that the carboxyl group in (29-1) first be converted to a thioacid. This conversion can be accomplished most conveniently by taking advantage of the rearrangement of a mixed anhydride of (30-1) with a carbonylthione. That transient anhydride... 

Polycarboxylic acid synthases. Several enzymes, including citrate synthase, the key enzyme which catalyzes the first step of the citric acid cycle, promote condensations of acetyl-CoA with ketones (Eq. 13-38). An a-oxo acid is most often the second substrate, and a thioester intermediate (Eq. 13-38) undergoes hydrolysis to release coenzyme A.199 Because the substrate acetyl-CoA is a thioester, the reaction is often described as a Claisen condensation. The same enzyme that catalyzes the condensation of acetyl-CoA with a ketone also catalyzes the second step, the hydrolysis of the CoA thioester. These polycarboxylic acid synthases are important in biosynthesis. They carry out the initial steps in a general chain elongation process (Fig. 17-18). While one function of the thioester group in acetyl-CoA is to activate the methyl hydrogens toward the aldol condensation, the subsequent hydrolysis of the thioester linkage provides for overall irreversibility and "drives" the synthetic reaction. 

The second five-carbon branched unit, in which the branch is one carbon further down the chain, is an intermediate in the biosynthesis of polyprenyl (isoprenoid) compounds and steroids. Three two-carbon units are used as the starting material with decarboxylation of one unit. Two acetyl units are first condensed to form acetoacetyl-CoA. Then a third acetyl unit, which has been transferred from acetyl-CoA onto an SH group of the enzyme, is combined with the acetoacetyl-CoA through an ester condensation. The thioester linkage to the enzyme is hydrolyzed to free the product 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This sequence is illustrated in Eq. 17-5. The thioester group of HMG-CoA is reduced to the... 

The thioester group (r )[C(=0)-S]) (Scheme 10) can be distinguished from the thionoester (i )[C(=S)—O]) by the carbonyl infrared stretching frequency (-1700 cm-1) and by the absence of the C=S bond (1200-1050 cm-1). In general, thioesters are both more readily synthesized and are more vulnerable to nucleophilic cleavage by virtue of a sulfur leaving group. 

Replacement of the peptide bond by a thioester group has been extensively applied in synthetic peptides used as enzyme substrates. Several classes of enzymes such as serine peptidases and metallo-endopeptidases are able to cleave efficiently thioester-modified amino acids and peptides. 61... 

Cross-linking is achieved by the activation of the Glu thioester group by silver ions, followed by nucleophilic attack of the N-terminal amino group from the other peptide. The process is repeated using the Glu a-thioester peptide to create a trimeric structure (Scheme... 

Benzo[ ]thiophene normally undergoes electrophilic substitution at the 3-position more rapidly than at the 2-position <1971AHC(13)284>, so both this and formation of the thioester group favor ketonization of 2-hydro-xybenzo[ ]thiophene which occurs 40 times faster than ketonization of 3-hydroxybenzo[ ]thiophene. The rapid rate of ketonization of the thio-ester enol 2-hydroxybenzo[ ]thiophene is also indicated by its 4.4-fold greater rate of ketonization compared to 2-hydroxyindene, which contrasts with what is found with 3-hydroxybenzo[. ]thiophene and 1-hydroxyindene <1986TL3275>. 

Fig. 4. Scheme of NCL. The mechanism allows the straightforward preparation of small proteins with native backbone structures from fully unprotected synthetic peptide building blocks. The initial tran -thioesterification step includes the chemo-selective reaction between one peptide with a C-terminal a-thioester group (peptide 1) and second peptide with an N-terminal cysteine residue (peptide 2). Generated thio-ester-linked intermediate spontaneously rearranges to form a native peptide bond at the site of ligation. 

Ttie thioester group of citryl CoA is hydrolyzed by a typical nucleophilic acyl substitution reaction to produce citrate plus coenzyme A. 

This type of modified lipopeptide cannot be deblocked under basic conditions because the labile palmitic acid thioester group would be preferentially hydrolyzed. The C-terminus of the peptide chain was selectively deprotected by removing the choline ester with choline esterase without affecting the palmitic acid thioester bond. The observed chemoselectivity here is exactly opposite to that found in nonenzymatic conversions. Some of the synthesized N-terminally deprotected lipopeptides, have been labeled with biotinand are expected to serve as anchors for a protein moiety in an artificial membrane. Butyrylcholine esterase mediated cleavage of the choline ester has been utilized l as the key step in the synthesis of S-palmitoylated peptides such as Myr-Gly-Cys(Plm)-Thr-Leu-Ser-Ala-OH, which represents the characteristic N-terminus of the a-subunit of human G o protein. 

The sensitivity of thioester groups to aminolysis by piperidine has prevented the use of thioester-based linkers for Fmoc SPPS. Two groups d have adapted a modified form of Kenner s acylsulfonamide safety-catch linkerf for the synthesis of C-terminal thioester peptides using Fmoc protocols (Scheme 8). This approach is promising and future studies will more fully analyze the limitations of the method. 

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