Acyl-coenzyme A thioesters

Thioesters play a paramount biochemical role in the metabolism of fatty acids and lipids. Indeed, fatty acyl-coenzyme A thioesters are pivotal in fatty acid anabolism and catabolism, in protein acylation, and in the synthesis of triacylglycerols, phospholipids and cholesterol esters [145], It is in these reactions that the peculiar reactivity of thioesters is of such significance. Many hydrolases, and mainly mitochondrial thiolester hydrolases (EC 3.1.2), are able to cleave thioesters. In addition, cholinesterases and carboxylesterases show some activity, but this is not a constant property of these enzymes since, for example, carboxylesterases from human monocytes were found to be inactive toward some endogenous thioesters [35] [146], In contrast, allococaine benzoyl thioester was found to be a good substrate of pig liver esterase, human and mouse butyrylcholinesterase, and mouse acetylcholinesterase [147],... 

Carboxylic acids. Aliphatic carboxylic acids (R—GOOH) are deprotonated at physiological pH (pH 7) and are therefore represented as R—COO. Thus, acetic acid (GHj—COOH) exists as acetate (CH3COO ) at pH 7. A variety of short chain mono-, di-and tricarboxylic acids are important intermediates in metabolism and may be present at low concentrations in all cells either as the acid or as a covalent adduct. Thus, acetate (C2) and malonate (C3) can exist as the key acyl-coenzyme A thioester intermediates acetylGoA and malonylCoA, respectively. Phosphoenolpyruvate (C3), 1,3-bisphosphoglyceric acid (C3) and 3-phosphoglyc,erate (C3) are key metabolic intermediates. 

Holden HM, Banning MM, Haller T, Gerlt JA. The crotonase superfamily divergently related enzymes that catalyze different reactions involving acyl coenzyme A thioesters. Acc. Chem. Res. 2001 34 145-157. 

Olsen J, Li C, Bjomsdottir I, Sidenius U, Hansen SH, Benet LZ (2005) In vitro and in vivo studies on acyl-coenzyme A-dependent bioactivation of zomepirac in rats. Chem Res Toxicol 18 1729—1736 Olsen J, Li C, Skonberg C, Bjomsdottir 1, Sidenius U, Benet LZ, Hansen SH (2007) Studies (m the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in... 

Aarsland, A. Berge, R.K. (1991) Biochem. Pharmacol., 41, 53-61. Peroxisome proliferating sulphur-and oxy-substituted fatty acid analogues are activated to acyl coenzyme A thioesters. 

Activated fatty acids fatty acyl coenzyme A thioesters which, as high energy compounds, have a high potential for group transfer. They are formed during fatty acid biosynthesis, or by the activation of free fatty acids. Acyl CoA synthetases catalyse formation of the CoA derivatives according to the... 

The mechanism for bacterial synthesis of PHA is not the simple dehydration reaction between alcohol and carboxyl groups. It is more complicated and involves the coenzyme A thioester derivative of the hydroxyalkanoic acid monomer (produced from the organic feedstock available to the bacteria) [Kamachi et al., 2001], Growth involves an acyl transfer reaction catalyzed by the enzyme PHA synthase (also called a polymerase) [Blei and Odian,... 

The fourth and last step of the /3-oxidation cycle is catalyzed by acyl-CoA acetyltransferase, more commonly called thiolase, which promotes reaction of /3-ketoacyl-CoA with a molecule of free coenzyme A to split off the carboxyl-terminal two-carbon fragment of the original fatty acid as acetyl-CoA The other product is the coenzyme A thioester of the fatty acid, now shortened by two carbon atoms (Fig. 17-8a). This reaction is called thiolysis, by analogy with the process of hydrolysis, because the /3-ketoacyl-CoA is cleaved by reaction with the thiol group of coenzyme A... 

Fatty acid biosynthesis. Activated as its coenzyme A thioester, the growing fatty acid (acyl-CoA) acylates malonyl-CoA in a malonic ester synthesis. Two carbon atoms are added, with the third lost as C02. Enzymatic reduction, dehydration, and further reduction gives a fatty acid that has been lengthened by two carbon atoms. 

Zacharias, D. E., Murray-Rust, P., Preston, R. M., and Glusker, J. P. The geometry of the thioester group and its implications for the chemistry of acyl coenzyme A. Arch. Biochem. Biophys. 222, 22-34 (1983). 

Acylated coenzyme A are thioesters, RCOSCoA, which are common intermediates used to transfer acyl groups and as a source of carbanions. 

All cases discussed in this section involve the reaction between an amine and an acyl group to yield an amide. The high-energy cofactor required is in most cases an acyl-coenzyme A derivative (acyl-S-CoA) where the acyl moiety is bound by a thioester linkage. 

Chiral inversion of the 2-APAS is presented in detail as a whole chapter (Chap. 8) in this book. However, a brief overview of its mechanism is presented here. The mechanism of the inversion reaction (Fig. 14) has been extensively investigated both in vitro and in vivo and involves stereoselective formation of the acyl-coenzyme A (CoA) thioester of the (i )-2-APA, via an adenosine monophosphate intermediate. Once formed, the (i )-profenyl-CoA thioester undergoes epimerization at the center of chirality in the profen moiety, which is thought to proceed via an enolate intermediate, to yield the corresponding (5)-profenyl-CoA thioester. Hydrolysis of the acyl-CoA thioesters results in the liberation of the free acid. The enzyme... 

It is known that there are several long-chain acyl-Coenzyme A synthetases (ACS). ACSl shares some similar catalytic and antigenic properties to pahnitoyl-CoA synthetase [29]. Nevertheless, there is evidence of multiple forms of microsomal coenzyme A ligase catalyzing the formation of 2-APA CoA thioesters with several binding sites as well as a catalytic site. For instance, R-ketoprofen CoA appears to be catalyzed by an alternative isoform of a microsomal CoA ligase that is not shared by fenoprofen and ibuprofen [30,31]. 

Key steps in the pathway are the activation of the fatty acid to a coenzyme A thioester, the a, -dehydrogenation of the acyl-CoA, the hydration of the resultant double bond, oxidation of the -hydroxyacyl-CoA and thiolytic cleavage of the -ketoacyl-CoA (Fig. 11.7). 

Thioester, acylmercaptan a compound of the general formula RS - CO-R,. The thioester (acylmercaptan) bond is energy-rich. All fatty acyl coenzyme A derivatives (activated fatty acids, e.g. acetyl-CoA) are T. During substrate phosphorylation on glyceral-dehyde 3-phosphate dehydrogenase a thiol group of the enzyme forms an energy-rich intermediate T. 

Enolate ion formation allows coenzyme A-bound acyl groups to serve as nucleophiles and to react at electrophilic centres. This permits thioesters to participate in the formation or degradation of carbon—carbon linkages by mechanisms analogous to the aldol condensation or more specifically the Qaisen type ester condensation. There are few available mechanisms for carbon—carbon bond formation or deavage which can be employed under biological reaction conditions, and pathways which depend on coenzyme A thioesters for this purpose are widespread. 

A convenient way to summarize the reactions of coenzyme A thioesters is by reviewing the )3-oxidation pathway for fatty adds". Fatty acid activation occurs by acylation of the coenzyme A thiol by way of an acyl adenylate. This is then dehydrogenated to an o,/3-enoyl acyl coenzyme A derivative by a flavin-dependent dehydrogenase. The ability of the adjacent carbonyl to provide resonance stabilization of the product appears to be an important aspect of this reaction. Such flavin-dependent dehydro- nations occur in other reaction sequences, but only where carbonyl resonance stabilization is possible. Water adds to the a,j8-enoyl thioester to generate a j8-hydroxy fatty acid derivative, a reaction facilitated by j8-carbonium ion stabilization in enoyl thioesters. The j3-hydroxyl is next... 

An intermediate enzyme-coenzyme A complex in which the energy of the thioester bond is preserved has been demonstrated. Here the coenzyme A thioester is involved in a transfer reaction quite different from its usual acyl donor role. Functionally this enzyme allows metabolically generated coenzyme A derivatives to be utilized directly for carboxylic acid activation, without intermediary formation of nudeoside triphosphates. 

A metabolically important route for the neration of acyl coenzyme A derivatives is through the oxidation of a-keto adds. The a-keto add dehydrogenase complexes, of which pyruvate dehydrogenase complex is typical, are large multienzyme aggregates. They carry out a comidex reaction sequence to be discussed in section III.D on lipoic acid. The overall reaction given below is an oxidative decarboxylation coupled to thioester formation. 

The final process for coenzyme A thioester synthesis is by the thiolytic cleavage of /8-keto acyl coen me A derivatives. The thiolase reaction is the principal metabolic process for degrading the hydrocarbon chain of fatty acids. 

Pigurs 2 Possible routes of the biosynthetic pathway of Bmt. Polyketide biosynthesis is assumed to take place in an entyme-bound form (ACT = acyl carrier protein). The produci compound A Is released from the Bmt symthase as a coenzyme A thioester. suggesring that subsequent transformation to Bmt takes ydacc upon this actistated intermediate. (From Ref. 36, with permission.)... 

---