Thioesters acyl transfer reaction

Thioesters are well known to racemize more easily than their oxygen counterparts, as well as being more labile towards acyl transfer reactions. The L-forms of... 

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,... 

Many other acyl transfer reactions are important cellular processes. Thioesters of fatty acids react with cholesterol, forming cholesteryl esters in an enzyme-catalyzed reaction (Figure 22.5). These esters are the principal form in which cholesterol is stored and transported in the body. Because cholesterol is a lipid, insoluble in the aqueous environment of the blood, it travels through the bloodstream in particles that also contain proteins and phospholipids. These particles are classified by their density. 

Other acyl group donors include thioesters and esters. As we will see in the final section of this chapter, acyl transfer reactions are very important in nature, particularly in the pathways responsible for breakdown of food molecules and harvesting cellular energy. 

The most abundant membranes in nature are the thylakoids inside chloroplasts of green plants. A surprising amount of lipid traffic is involved in the assembly of these membranes. Almost all the acyl chains that form the core of the photosynthetic membranes are first produced by fatty acid synthase in the chloroplast. In most plants these acyl chains are then exported to the ER where they become esterified to glycerol, desaturated while they are part of phosphatidylcholine and then are returned to the plastid. The exact mechanisms for the export and return of acyl chains are still uncertain although much has been learned (Chapter 17) [10]. The export from plastids across the chloroplast envelope membranes is known to involve a fatty acid intermediate, and probably is a channeled or facilitated process rather than free diffusion because only a tiny pool of free fatty acid is ever detected (A. Koo, 2004). An acyl-CoA synthetase on the envelope membrane is believed to quickly convert the exported fatty acid to a thioester form that is then a substrate for acyltransferases. Transfer of acyl groups to the ER may occur via diffusion of the acyl-CoAs however, recent evidence suggests this initial acyl transfer reaction involves acylation of lyso-phosphatidylcholine and may occur at the chloroplast envelope. 

Thioesters and oxoesters are similar in their rates of nucleophilic acyl substitution, except with amine nucleophiles for which thioesters are much more reactive. Many biological reactions involve nucleophilic acyl substitutions referred to as acyl transfer reactions. The thioester acetyl coenzyme A is an acetyl group donor to alcohols, amines, and assorted other biological nucleophiles. 

The general mechanism for acyl transfer reactions from thioesters is envisaged as a nucleophilic attack at the positively polarized carbonyl carbon, accompanied by or followed by thiol elimination. 

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... 

Step 5 of Figure 29.11 Acyl Transfer Acetyl dihydrolipoamide. a thioester, undergoes a nucleophilic acyl substitution reaction with coen/.yrne A to yield acetyl CoA plus dihydrolipoamide. The dihydrolipoamide is then oxidized back... 

Phosphopantetheine coenzymes form thioester linkages with acyl groups, which they activate for group transfer reactions. 

A comparison of Eq. 54 and Scheme 36 reveals that the nickel center performs two functions. First, the nickel center acts as mediator of the two electron-transfer reactions during which S—C bonds are cleaved and formed (36 —> 37 and 39 —> 40). Second, it facilitates the formation of an acyl group from an alkyl group and CO (38 —> 39). This reaction is expected to be favored when the nickel center has a coordination number lower than 5. A low coordination number of nickel also facilitates the final release of the thioester in the consecutive reaction of 39 with excess CO, because intermediates such as complex 42 can readily form. 

Steps 1-2 of Figure 29.5 Acyl Transfers The starting material for fatty-acid synthesis is the thioester acetyl CoA, the ultimate product of carbohydrate break-dowm, as wee ll sec in Section 29.6. The synthetic pathway begins with several primifiy reactions, w hich transport acetyl CoA and convert it into more reactive species. The first priming reaction is a nucleophilic acyl substitution reaction that converts acetyl CoA into acetyl ACP (acyl carrier protein). The reaction is catalyzed by ACP transacyJase. 

These partial reactions are freely reversible. In fact, the equilibrium constant for the sum of these reactions is close to 1. One high-transfer-potential compound is cleaved (between PP and AMP) and one high-transfer-potential compound is formed (the thioester acyl CoA). How is the overall reaction driven forward The answer is that pyrophosphate is rapidly hydrolyzed by a pyrophosphatase, and so the complete reaction is... 

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