Thioester biological reduction

Unlike other biological reductants, GSH forms a relatively stable Cr(VI) complex (thioester A in Scheme 3) at biologically relevant pH values (12, 98,... 

The aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be 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 acyl phosphate rather than an ester. 

The really unique reaction of the lipoate centre in ct-keto acid metabolism is the oxidative thioester formation from a thiamine-coordinated active aldehyde . Thiol transacetylase and dithiol-disulphide oxidation reduction roles are well-known attributes of other biological thiols. Unfortunately mechanistic studies on this reductive acylation of a cyclic disulphide have so far received little attention. Proposals that a lipoic acid-thiamine pyrophosphate compound was the functional entity in a-keto acid oxidation have been completely abandoned, but data supporting this concept remain unexplained. Investigations in this area might have some relevance for the reductive acylation process. 

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]. 

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. 

The first key discovery was that the entire cholesterol molecule was assembled by a sequential condensation of acetate molecules in their biologically activated form as coenzyme A (CoA) thioesters 10 (Bloch 1965). The key intermediate in the process was (3k)-mevalonic acid (MVA, 11), a six-carbon compound originally discovered as a byproduct in distillers solubles . Mevalonic acid is formed by the enzymatic reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA, 12) which in turn is formed by the head-to-tail condensation of three molecules of acetate (Figure 3.4) (Cornforth 1959). Mevalonic acid is enzymatically converted to IPP with loss of carbon dioxide, and it was... 

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