Thioester biological reactivity

Electronically, we find that strongly polarized acyl compounds react more readily than less polar ones. Thus, acid chlorides are the most reactive because the electronegative chlorine atom withdraws electrons from the carbonyl carbon, whereas amides are the least reactive. Although subtle, electrostatic potential maps of various carboxylic add derivatives indicate the differences by the relative blueness on the C-O carbons. Acyl phosphates are hard to place on this scale because they are not used in the laboratory, but in biological systems they appear to be somewhat more reactive than thioesters. 

Although transfer of the acetate group from its inital site, bound as a serine ester, to its reactive position on Cys-1305(a) can occur via an intermediate in which the acetate is attached to the phosphopantetheine thiol, evidence suggests that this reaction is not kinetically competent and that the biologically significant mechanism utilizes a direct transfer from Ser-819( ) to Cys-1305(a) [73]. Transfer of the malonyl group from its initial position at Ser-5421 (/3) to its reactive position as a phosphopantetheine thioester occurs directly [69]. 

The major classes of carbonyl compounds include aldehydes, ketones, carboxamides, esters, carboxylic acids and anhydrides, and carbonyl halides (acyl halides). These groups differ in the identity of the substituent X on the carbonyl group. At this point we concentrate on these examples, but a number of other carbonyl derivatives have important roles in synthetic and/or biological reactions. These other compounds include acyl cyanides, acyl azides, A-acylimidazoles, 0-aryl esters, and thioesters. The carbonyl compounds are arranged below in the order of the increasing reactivity toward nucleophilic addition. 

The thiol used in biological systems for the formation of thioesters is coenzyme A. The compound is written CoASH to emphasize that the thiol group is the reactive part of the molecule. 

The vitamin precursor of CoASH is pantothenate. We have seen that CoASH is used in biological systems to activate carboxylic acids by converting them into thioesters, which are much more reactive toward nucleophilic acyl substitution reac-... 

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. 

Thus the biological importance of the phosphopantetheine group as a catalytic centre is widespread. Numerous examples of the role of coenzyme A are known and the list of phosphopantetheine enzyme centres is growing. The principal reactive element is the thiol, although other attributes of the unique peptide will undoubtedly prove important. The thiol serves as the site of thioester formation and its particular chemical attributes facihtate acyl transfer, carbon chain modification and condensation reactions. The phosphopantetheine thiol represents the most... 

Treatment of the enzyme with acyl phosphate in the complete absence of reduced cofactor has allowed the thiol enzyme derivative to be prepared and separated from its reaction mixture. This in turn has permitted considerable characterization of the enzyme thiol. No special cofactor is involved. The thiol of a cysteine residue from the main peptide chain of the enzyme provides the reactive centre. This enzyme demonstrates that the acyl transfer role of thioesters in biological systems is not restricted to phosphopantetheine and dihydrolipoate derivatives. The reactions of the... 

Metal complexes are known to insert CO into carbon-sulfur bonds [118], even catalytically [119], Stoichiometric precedents exist for the formation offhioesters from nickel-alkyls, CO, and thiols [120], For example, NiMe2(bipy) reacts with thiols to afford mefhylnickel(ll) fhiolates, which carbonylate to afford acetyl-nickel(ll) fhiolates. These acetylnickel(II) thiolates reductively eliminate fhioester in the presence of CO [121], More biologically relevant is the reactivity of nickel acyls toward fhiolates, which gives fhe thioester concomitant with reduction to Ni(0) (Eq. 12.10) [122]. Thiolates are known to reduce Ni(II) to Ni(0) under an atmosphere of CO [123]. 

The aldehyde intermediate can he isolated if 1 equivalent of the less reactive reducing agent diisobutylaluminum hydride (DIBAH) is used instead of LiAlH4. The reaction is carried out at 78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or an acyl phosphate rather than an ester. We ll see an example in Section 16.8. 

In a different approach, the reactivity of thiazolium salts derived acyl anion equivalents (biological active aldehyde ) toward sulfur electrophiles has been examined recently (329) and provides a model for the thioester-forming step catalyzed by the lipoic acid containing enzymes. The results suggest that the biological generation of thioesters of coenzyme A from a-keto acids occurs via the direct reductive acylation of enzyme-bound lipoic acid by the active aldehyde, as already shown on page 453. 

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