Biological Function of Lipoic Acid

Lipoic acid participates in the coenzyme A (CoA)- and diphosphopyri-diiie nucleotide (DPN)-linkcd oxidative decarboxylation of a-keto acids [Eq. (3)]. There are alternate pathways of a-keto acid oxidation which do 

The decarboxylation reaction, Eq. (7), is visualized as a cleavage of the a-keto acid to yield CO2 and an enzyme-bound aldehyde-thiamine pyrophosphate (RCHO—TPP) compound, i.e., active aldehyde. There is now unequivocal evidence for this reaction since a pyruvic carboxylase (El) has been shown to be an essential component of the E. coli pyruvate dehydrogenation complex (Koike and Reed, 1961 Gounaris and Hager, 1961) and the nature of the aldehyde-TPP compound has been elucidated (Breslow, 1958 Breslow and McNelis, 1959 Krampitz et al., 1961 Holzer and Beaucamp, 1961 Carlson and Brown, 1961). 

MechaniHin of thuunine pyrophosphate action in the decarboxylation of pyruvate (Breslow, 1958). 

McNelis, 1959). This subject has been reviewed recently by Metzler (1960) and will not be discussed in detail here. In brief, Breslow postulated that thiamine pyropho.sphate ionizes at the 2-position of the thiazole ring, and that the thiazolium dipolar ion (IV) reacts with pyruvate to form an intermediate (2-laetylthiamine pyrophosphate) (V) which undergoes decarboxylation to produce 2-hydroxyethylthiamine pyrophosphate (VI, VII) (Fig. 2). Species (VI) is regarded as active acetaldehyde, and can 

The acyl-generation reaction, Eq. (8), has been visualized as a reductive acylation of protein-bound lipoic acid. As will be seen below, this reaction is now belitwod to consist of two steps an oxidation of the 2-hydroxyalkyl-thiamine pyrophcjsphatc to 2-aoylthiaminc pyrophosphate with a concomitant reduction of bound lipoic acid, and a transfer of (he acyl group of 2-acylthiamine pyrophosphate to the bound dihydrolipoic acid (Das el al., 19(il). An enzymatic component which contains bound lipoic acid and apparently catalyzes reactions (8) and (9) has been isolated from the E. mli pyruvate dehydrogenation complex (Koike and Reed, 1961). This component, designated lipoyl-Ea in Fig. 1, has been tentatively named lipoic reductase-transacetylase. 

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