Acetyl thioester

Figure 8-2. Pathway for synthesis of palmitate by the fatty acid synthase (FAS) complex. Schematic representation of a single cycle adding two carbons to the growing acyl chain. Formation of the initial acetyl thioester with a cysteine residue of the enzyme preceded the first step shown. Acyl carrier protein (ACP) is a component of the FAS complex that carries the malonate covalently attached to a sulfhydryl group on its phosphopantatheine coenzyme (-SH in the scheme).

A number of biosynthetically important enzymes promote aldol related Claisen additions of acetyl thioesters of coenzyme A (CoA) to ketones, often to a-oxoacids. This includes the citrate synthase (EC 4.1.3.7) which is one of the key enzymes in central metabolism, and several others involved in the biosynthesis... 

Terpenes are composed of isoprenyl (C-,) units and are conveniently grouped as monoter-penes (skeletal basis CI0 = 2X C-,), sesquiterpenes (G13 = 3X C3), diterpenes (C20 = 4X C-,), triterpenes (C3o = 6X C-,) and tetraterpenes (C40 = 8X G-j. The structures of some representative terpenes are shown in the Appendix (Section 3). Terpenes ultimately derive biosynthetically from acetate (C2) via the activated acetyl thioester (CH3—CO—S—X) acetyl-coenzyme A (acetylCoA CH3-CO-S-C0A) as outlined below (enzymes catalysing key steps being indicated in parentheses). 

It has been proposed by de Duve (see Further Reading) that primordial acetyl phosphate originates by reaction of acetyl-thioester with phosphate ions. According to the Iron-Sulfur World theory, phosphorylation energy may also result from a transfer of the redox energy of CO/H2S in the presence of amino acids (5), which received its first support by phosphate catalysis of peptide formation (16). Subsequently it was supported by the discovery of a formation of aminoacyl phosphate in reaction of phosphate with aminoacyl N-carboxyanhydride (21) ... 

According to a general rule of organic chemistry, reactions involving the smallest molecules are catalytically the most restrictive. This rule holds notably for the build-up of carbon skeletons with the arithmetic Cl -F Cl = C2 (e.g., C2 = glycine or acetyl thioester). Therefore, it may not come as a surprise that in the course of metabolic evolution, these most simple carbon fixation reactions may fall by the wayside. Under these conditions, an autotrophic carbon fixation metabolism can only be maintained by a metabolic cycle, which multiplies the C2 unit autocatalytically in the absence of its de novo synthesis. A prominent example is the reductive citric acid cycle (C2 -F Cl... 

Prsellinic acid, a common constituent of lichens, is synthesized from the condensation of acetyl thioester and malonyl thioester. If a lichen were grown on a medium containing acetate that was radioactively labeled with at the carbonyl carbon, which carbons would be labeled in orsellinic acid ... 

The other way to generate thioesters at the penultimate step of penem synthesis is acylation of silver thiolates 226. These compounds are conveniently obtained by cleavage of the corresponding trityl sulfides 225 with silver nitrate and methanol [51a, 144] trityl methyl ether and nitric acid (trapped by pyridine or, better, imidazole) are liberated in the process. Tetrahydropyranylthioethers 227 [145] and acetyl thioesters 228 [51a, 52] were also reported to be cleavable to the corresponding argentiothio-phosphoranes of general formula 226. 

A molecule of acetyl thioester and a molecule of malonyl thioester are the reactants for the first round in the biosynthesis of a fatty acid. 

The methylene group in the carboxylated species is much more reactive than the methyl group in acetyl thioesters and participates in a wide variety of Claisen-like condensations. Although these processes require enzyme catalysis, they may be written in simplified form, shown below. 

The thioacetate nucleophile can displace sulfonyl esters to produce acetyl thioesters from which the acetyl group can be removed to form thio sugars. The substitution of amino, sulfhydryl, or ethyl phosphite groups at C-5 of either pentoses or hexoses results in the substitution of nitrogen, sulfur, and phosphorus atoms, respectively, for the oxygen atom in the pyranose ring. 

The biosynthesis begins with acetyl-CoA, which is the most important intermediate in the breakdown of carbohydrates as well as fats and which has already occupied our attention. Since all reactions of jS-oxidation are reversible, it was thought at first that the catabolic reactions would be reversed by an excessive supply of reduced coenzymes and energy in the form of ATP (or acetyl-thioester). The organism, however, does not appear to use this possibility, except perhaps to a minor extent, and instead prefers to follow an alternate route for synthesis. 

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