Acylation thiols

The primary role of pantothenic acid is in acyl group activation for lipid metabolism, involving thiol acylation of CoA or of ACP, both of which contain 4-phosphopantotheine, the active group of which is /3-mercaptoethylamine. CoA is essential for oxidation of fatty acids, pyruvate and a-oxogutarate, for metabolism of sterols, and for acetylation of other molecules, so as to modulate their transport characteristics or functions. Acyl carrier protein, which is synthesized... 

Thioesters undergo the same kinds of reactions as esters and by similar mechanisms Nucleophilic acyl substitution of a thioester gives a thiol along with the product of acyl transfer For example... 

Thioester (Section 20 13) An S acyl denvative of a thiol a compound of the type... 

The schemes depicted in Figure 7 contrast two complimentary approaches to cefotiam (50) in which the timing of the introduction of the C-3 substituent differs. In Route A the heterocycHc thiol C-3 substituent is introduced even before the removal of the aminoadipoyl acyl side chain. The acetonylacetyl C-3 substituent was introduced because it gave considerably higher yields and cleaner product in the nucleophilic displacement step than the corresponding acetoxy, and the starting material, deacetylcephalosporin C (5) was readily available from a fermentation process (190,191). 

Scheme 68 shows the conversion of the phenoxymethylpenicillin-derived disulfide (see Scheme 10) to penem derivative (91) (78JA8214). Of particular interest in this sequence is the reductive acylation step to afford (89) and the Wittig ring closure to give (90). The rate of the latter reaction was found to be greatly infiuenced by the steric and electronic character of both the thiol ester and the carboxyl blocking group. 

Pyrimidine-2-sulfonyl chloride, 4,6-dimethyl-reactions, 3, 97 Pyrimidinesulfonyl halides reactions, 3, 97 Pyrimidinethiols S-acylation, 3, 95 S-alkylation, 3, 94 oxidation, 3, 94 synthesis, 3, 135 Pyrimidine-5-thiols oxidation, 3, 94 synthesis, 3, 136... 

Several additional points should be made. First, although oxygen esters usually have lower group-transfer potentials than thiol esters, the O—acyl bonds in acylcarnitines have high group-transfer potentials, and the transesterification reactions mediated by the acyl transferases have equilibrium constants close to 1. Second, note that eukaryotic cells maintain separate pools of CoA in the mitochondria and in the cytosol. The cytosolic pool is utilized principally in fatty acid biosynthesis (Chapter 25), and the mitochondrial pool is important in the oxidation of fatty acids and pyruvate, as well as some amino acids. 

The final step in the /3-oxidation cycle is the cleavage of the /3-ketoacyI-CoA. This reaction, catalyzed by thiolase (also known as j8-ketothiolase), involves the attack of a cysteine thiolate from the enzyme on the /3-carbonyI carbon, followed by cleavage to give the etiolate of acetyl-CoA and an enzyme-thioester intermediate (Figure 24.17). Subsequent attack by the thiol group of a second CoA and departure of the cysteine thiolate yields a new (shorter) acyl-CoA. If the reaction in Figure 24.17 is read in reverse, it is easy to see that it is a Claisen condensation—an attack of the etiolate anion of acetyl-CoA on a thioester. Despite the formation of a second thioester, this reaction has a very favorable A).q, and it drives the three previous reactions of /3-oxidation. 

FIGURE 24.17 The mechanism of the thiolase reaction. Attack by an enzyme cysteine thiolate group at the /3-carbonyl carbon produces a tetrahedral intermediate, which decomposes with departure of acetyl-CoA, leaving an enzyme thioester intermediate. Attack by the thiol group of a second CoA yields a new (shortened) acyl-CoA. 

The salts of the thiol react with alkyl and acyl halides to form alkyl or acyl derivatives (Table II). For a discussion of the constitution of these compounds see Section IV, D. 

Lieber et al. have discussed whether the compound obtained from the sodium salt of the thiol and methyl iodide is an A- or an /S-deriv-ative and have proved that it is the /S-derivative by syntheses of this compound from methyl dithiocarbazinate (CHgS—CS—NH—NH2) and nitrous acid. The acyl derivatives are, however, formulated as A-acylthiatriazoline-6-thiones, because they are decomposed to form acylisothiocyanates. Lieber et have shown that thiocyanates... 

Aminosodium salt and acylated with 1 H-tetrazole-1 -acetyl chloride. The acetoxy group is then displaced by reaction with 5-methyl-1,3-4-thi-adiazole-2-thiol in buffer solution. The product acid is converted to the sodium salt by NaHCOa. 

Acyl CoA s, such as acetyl CoA, are the most common thioesters in nature. Coenzyme A, abbreviated CoA, is a thiol formed by a phosphoric anhydride linkage (0 = P—O—P=0) between phosphopantetheine and adenosine 3, 5 -bisphosphate. (The prefix "bis" means "two" and indicates that adenosine 3, 5 -bisphosphate has two phosphate groups, one on C3 and one on C5. ) Reaction of coenzyme A with an acyl phosphate or acyl adenylate... 

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