Pyruvate dehydrogenase decarboxylating

Lipoic acid is an acyl group carrier. It is found in pyruvate dehydrogenase zard a-ketoglutarate dehydrogenase, two multienzyme complexes involved in carbohydrate metabolism (Figure 18.34). Lipoie acid functions to couple acyl-group transfer and electron transfer during oxidation and decarboxylation of a-keto adds. 

Many metabolic fuels are oxidized in the mitochondrial matrix. Pyruvate is oxidatively decarboxylated to acetyl-CoA by the pyruvate dehydrogenase complex (PDH)... 

Figure 17-5. Oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex. Lipoic acid is joined by an amide link to a lysine residue of the transacetylase component of the enzyme complex. It forms a long flexible arm, allowing the lipoic acid prosthetic group to rotate sequentially between the active sites of each of the enzymes of the complex. (NAD nicotinamide adenine dinucleotide FAD, flavin adenine dinucleotide TDP, thiamin diphosphate.)...

Fig. 3. Generation of propionyl-CoA from the isoleucine biosynthetic pathway. The intermediate 2-ketobutyrate can be decarboxylated by either the 2-oxoacid dehydrogenase complex or at low efficiency by the pyruvate dehydrogenase complex. Inhibition of the threonine deaminase by isoleucine and of the acetolactate synthase by herbicides are indicated with dashed arrows...

Similarly, the pyruvate dehydrogenase complex (PDC) can be activated directly by electrogenerated methyl viologen radical cations (MV +) as mediator. Thus, the naturally PDC-catalyzed oxidative decarboxylation of pyruvic acid in the... 

A. P. Zeng, J. Modak, and W. D. Deckwer, Nonlinear dynamics of eucaryotic pyruvate dehydrogenase multienzyme complex Decarboxylation rate, oscillations, and multiplicity. Biotechnol. Prog. 18(6), 1265 1276 (2002). 

Thiamine pyrophosphate is a coenzyme for several enzymes involved in carbohydrate metabolism. These enzymes either catalyze the decarboxylation of oi-keto acids or the rearrangement of the carbon skeletons of certain sugars. A particularly important example is provided by the conversion of pyruvic acid, an oi-keto acid, to acetic acid. The pyruvate dehydrogenase complex catalyzes this reaction. This is the key reaction that links the degradation of sugars to the citric acid cycle and fatty acid synthesis (chapters 16 and 18) ... 

The intermediary metabolism has multienzyme complexes which, in a complex reaction, catalyze the oxidative decarboxylation of 2-oxoacids and the transfer to coenzyme A of the acyl residue produced. NAD" acts as the electron acceptor. In addition, thiamine diphosphate, lipoamide, and FAD are also involved in the reaction. The oxoacid dehydrogenases include a) the pyruvate dehydrogenase complex (PDH, pyruvate acetyl CoA), b) the 2-oxoglutarate dehydrogenase complex of the tricarboxylic acid cycle (ODH, 2-oxoglutarate succinyl CoA), and c) the branched chain dehydrogenase complex, which is involved in the catabolism of valine, leucine, and isoleucine (see p. 414). 

Initially, pyruvate dehydrogenase [El] catalyzes the decarboxylation of pyruvate and the transfer of the resulting hydroxyethyl residue to thiamine diphosphate (TPP, la). The same enzyme then catalyzes oxidation of the TPP-bound hydroxyethyl group to yield an acetyl residue. This residue and the reducing equivalents obtained are then transferred to lipoamide (1b). 

The tricarboxylic acid cycle not only takes up acetyl CoA from fatty acid degradation, but also supplies the material for the biosynthesis of fatty acids and isoprenoids. Acetyl CoA, which is formed in the matrix space of mitochondria by pyruvate dehydrogenase (see p. 134), is not capable of passing through the inner mitochondrial membrane. The acetyl residue is therefore condensed with oxaloacetate by mitochondrial citrate synthase to form citrate. This then leaves the mitochondria by antiport with malate (right see p. 212). In the cytoplasm, it is cleaved again by ATP-dependent citrate lyase [4] into acetyl-CoA and oxaloacetate. The oxaloacetate formed is reduced by a cytoplasmic malate dehydrogenase to malate [2], which then returns to the mitochondrion via the antiport already mentioned. Alternatively, the malate can be oxidized by malic enzyme" [5], with decarboxylation, to pyruvate. The NADPH+H formed in this process is also used for fatty acid biosynthesis. 

Malic enzyme (malate dehydrogenase (decarboxylating), EC 1.1.1.39) catalyzes reversible oxidative decarboxylation of malate to pyruvate. The enzyme uses NAD+ as an electron acceptor, but it is also able to utilize NADP+ with lower affinity (Drmota et al. 1996). With a subunit size of approximately 63 kDa, the Trichomonas hydrogenosomal malic enzyme belongs to the family of large, eukaryotic type of malic enzymes. In contrast, the approximately 40-kDa-subunit malic enzyme, located in the cytosol, belongs... 

In the first step, pyruvate is decarboxylated in an irreversible reaction catalyzed by pyruvate decarboxylase. This reaction is a simple decarboxylation and does not involve the net oxidation of pyruvate. Pyruvate decarboxylase requires Mg24" and has a tightly bound coenzyme, thiamine pyrophosphate, discussed below. In the second step, acetaldehyde is reduced to ethanol through the action of alcohol dehydrogenase, with... 

Figure 16-6 shows schematically how the pyruvate dehydrogenase complex carries out the five consecutive reactions in the decarboxylation and dehydrogenation of pyruvate. Step CD is essentially identical to the reaction catalyzed by pyruvate decarboxylase (see Fig. 14-13c) C-l of pyruvate is released as C02, and C-2, which in pyruvate has the oxidation state of an aldehyde, is attached to TPP as a hydroxyethyl group. This first step is the slowest and therefore limits the rate of the overall reaction. It is also the point at which the PDH complex exercises its substrate specificity. In step (2) the hydroxyethyl group is oxidized to the level of a car-...

Oxidative decarboxylation of pyruvate by pyruvate dehydrogenase complex is an important pathway in tissues with a high oxidative capacity, such as cardiac muscle (Figure 8.24). Pyruvate dehydrogenase irreversibly converts pyruvate, the end product of glycolysis, into acetyl CoA, a major fuel for the tricarboxylic acid cycle (see p. 107) and the building block for fatty acid synthesis (see p. 181). 

The conversion of pyruvate to ethanol occurs by the two reactions summarized in Figure 8.24. The decarboxylation of pyruvate by pyruvate decarboxylase occurs in yeast and certain microorganisms, but not in humans. The enzyme requires thiamine pyrophosphate as a coenzyme, and catalyzes a reaction similar to that described for pyruvate dehydrogenase (see p. 108). 

Pyruvate is decarboxylated to form a hydroxyethyl derivative bound to the reactive carbon of thiamine pyrophosphate, the coenzyme of pyruvate dehydrogenase. 

---