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Dihydrolipoic dehydrogenase

Figure 11.2 Reaction sequences catalyzed by 2-oxoacid dehydrogenase complex Pyruvate dehydrogenase complex (PDC) and a-ketoglutarate dehydrogenase complex (aKGDC) catalyze the oxidative decarboxylation of pyruvate (R = CH3) and a-ketoglutarate (R = CH2CH2COOH) to Acetyl-CoA and succinyl CoA respectively. Three component enzymes 2-oxoacid (pyruvate/a-ketoglutarate) decarboxylase, lipoate acetyltransferase/succinyltransferase, dihydrolipoate dehydrogenase as well as five cofactors, namely (1) thiamine pyrophosphate (TPP) and its acylated form, (2) lipoamide (LipS2), reduced form and acylated form, (3) flavin adenine dinucleotide (FAD) and its reduced form, (4) nicotinamide adenine dinucleotide (NAD ) and its reduced form, and (5) coenzyme A (CoASH) and its acylated product are involved. Figure 11.2 Reaction sequences catalyzed by 2-oxoacid dehydrogenase complex Pyruvate dehydrogenase complex (PDC) and a-ketoglutarate dehydrogenase complex (aKGDC) catalyze the oxidative decarboxylation of pyruvate (R = CH3) and a-ketoglutarate (R = CH2CH2COOH) to Acetyl-CoA and succinyl CoA respectively. Three component enzymes 2-oxoacid (pyruvate/a-ketoglutarate) decarboxylase, lipoate acetyltransferase/succinyltransferase, dihydrolipoate dehydrogenase as well as five cofactors, namely (1) thiamine pyrophosphate (TPP) and its acylated form, (2) lipoamide (LipS2), reduced form and acylated form, (3) flavin adenine dinucleotide (FAD) and its reduced form, (4) nicotinamide adenine dinucleotide (NAD ) and its reduced form, and (5) coenzyme A (CoASH) and its acylated product are involved.
A significant advance in understanding of the mechanism of the dihydrolipoic dehydrogenase reaction resulted from the discovery by Massey (1958) that the classic flavoprotein first isolated by Straub (1939), and widely known as Straub s diaphorase, behaves as a powerful dihydrolipoic dehydrogenase. Diaphorase activity was measured with ferricyanide as electron acceptor, Eq. (27), and dihydrolipoic dehydrogenase activity by... [Pg.21]

Searls and Sanadi (1960a) determined the reduction potential of the pig heart dihydrolipoic dehydrogenase from the extent of its reduction at different DPNH DPN ratios. The value is between —0.332 and —0.320 volt at pH 7.0 and 25°C. Thus the reduction potential of the flavoprotein is close to that of the DPNH-DPN system, —0.320 volt at pH 7.0 and 25°C (Burton and Wilson, 1953), and the Lip(SH)2-LipS2 system, —0.325 volt at pH 7.0 and 25°C (see Section II, A). This is consistent with the ready reversibility of reaction (26) as well as the high initial reaction rates in both directions. It would appear that DPN is the physiological electron acceptor for the a-keto acid dehydrogenation complexes in vivo and that the DPNH formed is reoxidized by way of the electron transport chain. However, the... [Pg.22]

Searls and Sanadi (1959, 1960a) and Massey et al. (1960) observed an increase in absorbancy in the region between 500 and 600 mju (maximum at 530 m/i), concomitant with a decrease at 455 mju, on reduction of pig heart dihydrolipoic dehydrogenase with DPNH and with dihydrolipoic acid.A similar effect was noted previously by Savage (1957) on reduction of Straub s diaphorase with DPNH. These results recalled similar observations by Beinert (1957) with other flavoproteins which were attributed to the formation of a flavin semiquinone. Massey ei al. (1960) have made a detailed study of the stoichiometry of formation of the 530-mju band and the kinetics of its formation and disappearance under a variety of conditions, and attributed it to a flavin semiquinone which is an obligatory intermediate in the catalytic cycle of the enzyme. Addition of p-chloro-mercuriphenyl sulfonate to the partially reduced flavoprotein resulted in disappearance of the red color and further reduction of the flavin. This observation was interpreted as indicating that the flavin semiquinone is stabilized by interaction with a protein sulfhydryl group. [Pg.23]

Mutation of the dihydrolipoate reductase component impairs decarboxylation of branched-chain a-keto acids, of pyruvate, and of a-ketoglutarate. In intermittent branched-chain ketonuria, the a-keto acid decarboxylase retains some activity, and symptoms occur later in life. The impaired enzyme in isovaleric acidemia is isovaleryl-CoA dehydrogenase (reaction 3, Figure 30-19). Vomiting, acidosis, and coma follow ingestion of excess protein. Accumulated... [Pg.259]

Lipoic acid (the other names are a-lipoic acid or thioctic acid) (Figure 29.9) is a natural compound, which presents in most kinds of cells. Lipoic acid (LA) is contained in many food products, in particular in meat, but it is also synthesized in human organism from fatty acids. Earlier, it has been shown that in humans lipoic acid functions as a component of the pyruvate dehydrogenase complex. However, later on, attention has been drawn to the possible antioxidant activity of the reduced form of lipoic acid, dihydrolipoic acid (DHLA) (Figure 29.9). [Pg.873]

Lewisite is the most important of the organo-arseni-cal CW agents. Exposure to lewisite is quite painful, and onset of symptoms occurs rapidly (seconds to minutes) (31) in contrast to sulfur mustard for which a latency period occurs of several hours between exposure and symptoms (32). Although it is not known to have been used as a CW agent, lewisite is still considered a potential threat due to the relative ease of production and its rapid onset of action. Moreover, substantial stockpiles of lewisite are present in the United States, Russia, and in China abandoned by the Japanese Imperial Army. This may constitute a potential hazard for public health (33). The toxicity of lewisite is inter alia caused by the high affinity for the vicinal di-thiol system present in dihydrolipoic acid, a component of the pyruvate dehydrogenase complex, as is the case for other arsenicals (34). This prevents the formation of acetyl coenzyme A from pyruvate. [Pg.441]

Pyruvate produced by the glycolytic pathway may be transported into the mitochondria (via an antiport with OH"), where it is converted to acetyl-CoA by the action of the enzyme complex pyruvate dehydrogenase. The pertinent enzyme activities are pyruvate dehydrogenase (PD), lipoic acid acetyltransferase, and dihydrolipoic acid dehydrogenase. In addition, several cofactors are utilized thiamine pyrophosphate (TPP), lipoic acid, NAD+, Co A, and FAD. Only Co A and NAD+ are used in stoichiometric amounts, whereas the others are required in catalytic amounts. Arsenite and Hg2+ are inhibitors of this system. The overall reaction sequence may be represented by Figure 18.5. The NADH generated may enter the oxidative phosphorylation pathway to generate three ATP molecules per NADH molecule reduced. The reaction is practically irreversible its AGq = -9.4 kcal/mol. [Pg.471]

The kinetics of the half-reactions for pig heart lipoamide dehydrogenase, i.e., the conversion of enzyme to EHj by NADH or dihydrolipo-amide and the reoxidation of EH by NAD or lipoamide derivatives, have been measured by rapid reaction spectrophotometry (24, 137). Reduction of the enzyme by NADH and reoxidation of EH2 by NAD are complete in the dead time of the instrument which is 3 msec. The rate of reduction of the enzyme by dihydrolipoamide is rate determining in the overall reaction and is 33,000 min" at infinite reductant concentration the same rate is determined by conventional kinetics at infinite concentration of both substrates (24) ... [Pg.115]

The accumulation of pyruvic acid in treated Aspergillus points to the molecular site of action of DMDC, oxine, and pyrithione, namely catalysis of the oxidative destruction of dihydrolipoic acid [thioctic acid 2.28) (Sijpesteijn and Janssen, 1959). This is the essential coenzyme for oxidative decarboxylation of pyruvic acid by dihydrolipoylacetyltransferase, a component of the multienzyme complex known as pyruvate dehydrogenase. [Pg.478]


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