Production of Acetyl-CoA (Activated Acetate):- The Pyruvate Dehydrogenase Complex Requires Five Coenzymes
The combined dehydrogenation and decarboxylation of pyruvate to the acetyl group of acetyl-CoA (Fig. 16–2) requires the sequential action of three different en zymes and five different coenzymes or prosthetic groups—thiamine pyrophosphate (TPP), flavin adenine dinucleotide (FAD), coenzyme A (CoA, sometimes de noted CoA-SH, to emphasize the role of the OSH group), nicotinamide adenine dinucleotide (NAD), and lipoate. Four different vitamins required in human nutrition are vital components of this system: thiamine (in TPP), riboflavin (in FAD), niacin (in NAD), and pantothenate (in CoA). We have already described the roles of FAD and NAD as electron carriers (Chapter 13), and we have encountered TPP as the coenzyme of pyruvate decarboxylase (see Fig. 14–13). Coenzyme A (Fig. 16–3) has a reactive thiol (-SH) group that is critical to the role of CoA as an acyl carrier in a number of metabolic reactions. Acyl groups are covalently linked to the thiol group, forming thioesters. Because of their relatively high standard free energies of hydrolysis (see Figs 13–6, 13–7), thioesters have a high acyl group transfer potential and can donate their acyl groups to a variety of acceptor molecules. The acyl group attached to coenzyme A may thus be thought of as “activated” for group transfer.
The fifth cofactor of the PDH complex, lipoate (Fig. 16–4), has two thiol groups that can undergo reversible oxidation to a disulfide bond (-S-S-), similar to that between two Cys residues in a protein. Because of its capacity to undergo oxidation-reduction reactions, lipoate can serve both as an electron hydro gen carrier and as an acyl carrier, as we shall see.
FIGURE 16–4 Lipoic acid (lipoate) in amide linkage with a Lys residue. The lipoyllysylmoiety is the prosthetic group of dihydrolipoyl transacetylase (E2 of the PDH complex). The lipoyl group occurs in oxidized (disulfide) and reduced (dithiol) forms and acts as a carrier of both hydrogen and an acetyl (or other acyl) group.
