Oxidation of a-keto acids

The chemical aspect of the coenzymatic action of a-lipoic acid is to mediate the transfer of electrons and acti-vated acyl groups resulting from the decarboxylation and oxidation of a-keto acids within the complexes. In this process, lipoic acid is itself transiently reduced to dihydrolipoic acid (see fig. 10.12), and this reduced form is the acceptor of the activated acyl groups. Its dual role of electron and acyl-group acceptor enables lipoic acid to couple the two processes. 

The active aldehyde intermediate then interacts with thi-octic acid to form acetyl-thioctatc. which is responsible for acetylating CoA-SH to form acetyl-CoA. In deficiency states, the oxidation of a-keto acids is decreased, resulting in increased pyruvate levels in the blood. 

Many alcoholics such as Al Martini develop thiamine deficiency because alcohol inhibits the transport of thiamine through the intestinal mucosal cells. In the body, thiamine is converted to thiamine pyrophosphate (TPP). TPP acts as a coenzyme in the decarboxylation of a-keto acids such as pyruvate and a-ketoglutarate (see Fig. 8.11) and in the utilization of pentose phosphates in the pentose phosphate pathway. As a result of thiamine deficiency, the oxidation of a-keto acids is impaired. Dysfunction occurs in the central and peripheral nervous system, the cardiovascular system, and other organs. 

TPP-dependent enzymes are involved in oxidative decarboxylation of a-keto acids, making them available for energy metabolism. Transketolase is involved in the formation of NADPH and pentose in the pentose phosphate pathway. This reaction is important for several other synthetic pathways. It is furthermore assumed that the above-mentioned enzymes are involved in the function of neurotransmitters and nerve conduction, though the exact mechanisms remain unclear. 

Summarizing the results obtained by controlled potential electrolysis and polarography, the reaction process for the electrolytic evolution of CO2 was estimated to be as follows the first step was one electron transfer from DMFC in NB to FMN in W as in Eq. (7). The second step was the catalytic reduction of O2 by FMNH as in Eq. (8). The final step was the oxidation of pyruvic acid by the reduction product of O2, H2O2, in W as in Eq. (9), well-known as an oxidative decarboxylation of a-keto acids [43] ... 

A good example of the simplicity and power of the chemistry to rapidly construct complex systems is provided by the Kolbe dimerization of (55) as the key step of a total synthesis of the triterpene (+)-Q -onocerin (57 Scheme 14) [33], Thus, oxidation of (+)-hydroxy keto acid (55) in methanol containing a trace of sodium methoxide and at a temperature of 50 C, followed by acylation and chromatography, provided (+)-diacetoxydione (56) in a 40% yield. 

Two sources of acyl radicals have proved to be useful for the homolytic acylation of protonated heteroaromatic bases the oxidation of aldehydes and the oxidative decarboxylation of a-keto acids. The oxidation... 

Protonated pyridines and derivatives readily undergo acylation at C-2 or C-4 (Table 28) (76MI20503). Acyl radicals are usually generated either by hydrogen abstraction from aldehydes (Scheme 210), or by oxidative decarboxylation of a-keto acids (Scheme 211). In the former case (Scheme 210) with acridine as the substrate, reduction can take place to give a dihydroacridine. 

Anodic oxidation of a carboxylic acid generates a carbenium ion at the a-carbon. This contrapolarization enables a facile fragmentation of y-keto acids [255],... 

Acyl radicals obtained by the oxidation of aldehydes or the oxidative decarboxylation of a-keto acids react selectively at the a- or y-position of the protonated heterocyclic nitrogen. Pyridines, quinolines, pyrazines and quinoxalines all react as expected yields are typically 40 to 70%. Similarly, pyridines can be carbamoylated in acid media at C-2 (Scheme 38). 

TPP-dependent enzymes catalyze either simple decarboxylation of a-keto acids to yield aldehydes (i.e. replacement of C02 with H+), or oxidative decarboxylation to yield acids or thioesters. The latter type of reaction requires a redox coenzyme as well (see below). The best known example of the former non-oxidative type of decarboxylation is the pyruvate decarboxylase-mediated conversion of pyruvate to acetaldehyde and C02. The accepted pathway for this reaction is shown in Scheme 10 (69MI11002, B-70MI11003, B-77MI11001>. 

Oxidative decarboxylations of a-keto acids are mediated by either enzymes having more than one cofactor or complex multienzyme systems utilizing a number of cofactors. For example, pyruvate oxidase uses TPP and FAD as coenzymes, the function of the latter being to oxidize the intermediate (41). Conversion of pyruvate to acetyl-CoA requires a multienzyme complex with the involvement of no less than five coenzymes, TPP, CoA, dihydrolipoate, FAD and NAD+ (74ACR40). 

Oxidation of a-amino acids to keto acids catalysed by D- and L-amino acid oxidases Oxidation of NADH via the cytochrome system catalyzed by cytochrome reductase Energy production via the TCA or Krebs cycle catalyzed by succinate dehydrogenase Fatty acid oxidation catalyzed by acyl-coenzyme A dehydrogenases Synthesis of fatty acids from acetate (80,81)... 

Decarboxylation of a-keto acids is a feature of primary metabolism, e.g. pyruvic acid -> acetaldehyde in glycolysis, and pyruvic acid acetyl-CoA, an example of overall oxidative decarboxylation prior to entry of acetyl-CoA... 

The a-keto acid-dependent enzymes [206-208] catalyze a diverse array of reactions (Figure 26) involving functionalization of an unactivated C—H bond concomitant with the oxidative decarboxylation of a keto acid. For the hydroxylation... 

The total oxygen-scavenging capacity (TOSC) assay is based on the oxidation of a-keto-y -methiolbutyric acid (KMBA) to ethylene. Ethylene formation is monitored by gas chromatography in the course of reaction and areas below the kinetic curves for control sample and analyzed sample are compared. The oxidant is usually ABAP, but other oxidants were also used and compared (R5, W12). 

Electron transfer between pyridine nucleotides and disulfide compounds is catalyzed by several fiavoproteins and three of these are well characterized. Lipoamide dehydrogenase functions in the oxidative decarboxylation of a-keto acids catalyzing the reoxidation of reduced lipoate by NAD+ (18, 19). Glutathione reductase catalyzes electron transfer between NADPH and glutathione ZO-22). Thioredoxin reductase catalyzes the reduction of thioredoxin by NADPH (5) thioredoxin is a protein of 12,000 molecular weight containing a single cystine residue which is the electron acceptor S3). 

The oxidative photoelectrochemical synthesis of amino acids from simple molecules (ammonia, methane, and water) has been reported [133, 134]. Low efficiencies were observed in the conversion of mixtures of methane, ammonia, and water to several amino acids on platinized Ti02. Amino acids and peptides were formed when glucose replaced methane as the carbon source in a parallel experiment. Higher quantum efficiencies (20-40 %) were observed in the conversion of a-keto acids or a-hydroxy acids to the corresponding a-amino acids, and moderate levels of enantiomeric selectivity (optical yields of about 50 %) were reported when ehiral starting materials were employed. 

The tricyclic alcohol (130) is an intermediate in the synthesis of rimuene. Hydroboronation of its tetrahydropyranyl ether and then oxidation with iodine and lead tetra-acetate afforded the 6—18 ether which could be cleaved and oxidized to a keto-acid. Such derivatives might form suitable intermediates for the synthesis of the rosane lactones. O-MethyI-14-methyl podocarpic acid has been synthesized "" by a conventional ring a + ring c route. 

Oxidative decarboxylation of a-keto acids such as pyruvate and a -ketoglutarate. 

Figure 4-9. Role of lipoic acid in oxidative decarboxylation of a-keto acids.

Thiamine is required by the body as the pyrophosphate (TPP) in two general types of reaction, the oxidative decarboxylation of a keto acids catalyzed by dehydrogenase complexes and the formation of a-ketols (ketoses) as catalyzed by transketolase, and as the triphosphate (TTP) within the nervous system. TPP functions as the Mg -coordinated coenzyme for so-called active aldehyde transfers in mul-tienzyme dehydrogenase complexes that affect decarboxyia-tive conversion of a-keto (2 oxo) acids to acyl-coenzyme A (acyl-CoA) derivatives, such as pyruvate dehydrogenase and a-ketoglutarate dehydrogenase. These are often localized in the mitochondria, where efficient use in the Krebs tricarboxylic acid (citric acid) cycle follows. 

Thiamine pyrophosphate has two important coenzyme roles, both of which focus mostly on carbohydrate metabolism (Figs. 8.26 and 8.27). The active portion of the coen- rae is the thiazole ring. The first step in the oxidative decarboxylation of a-keto acids requires TPP. The two most common examples are pyruvate and a-ketoglutarate, oxidatively decarboxyatedto acetyl CoA and succinyl CoA, respectively. The same reaction is found in the metabolism of the branched-chain amino acids valine, isoleucine, leucine, and methionine. In all cases, TPP is a coenzyme in a mitochondrial multienzyme complex, consisting of TPP, lipoic acid, coenzyme A, FAD, and NAD. Note the number of vitamins required for the oxidative decarboxylation of a-keto acids thiamine (TPP), pantothenic acid (coenzyme A), riboflavin (FAD),and niacin (NAD). 

---