Lipoic acid functional form

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). 

The oxidised and reduced forms of lipoic acid are given in figure 6.11. Lipoic acid functions as a coenzyme in pyruvate and a-ketoglutarate dehydrogenase multienzyme complexes. 

The coenzyme form of pantothenic acid is coenzyme A and is represented as CoASH. The thiol group acts as a carrier of acyl group. It is an important coenzyme involved in fatty acid oxidation, pyruvate oxidation and is also biosynthesis of terpenes. The epsilon amino group of lysine in carboxylase enzymes combines with the carboxyl carrier protein (BCCP or biocytin) and serve as an intermediate carrier of C02. Acetyl CoA pyruvate and propionyl carboxylayse require the participation of BCCP. The coenzyme form of folic acid is tetrahydro folic acid. It is associated with one carbon metabolism. The oxidised and reduced forms of lipoic acid function as coenzyme in pyruvate and a-ketoglutarate dehydrogenase complexes. The 5-deoxy adenosyl and methyl cobalamins function as coenzyme forms of vitamin B12. Methyl cobalamin is involved in the conversion of homocysteine to methionine. 

The metabolic functions of pantothenic acid in human biochemistry are mediated through the synthesis of CoA. Pantothenic acid is a structural component of CoA. which is necessary for many important metabolic processes. Pantothenic acid is incorporated into CoA by a. series of five enzyme-catalyzed reactions. CoA is involved in the activation of fatty acids before oxidation, which requires ATP to form the respective fatty ocyl-CoA derivatives. Pantothenic acid aI.so participates in fatty acid oxidation in the final step, forming acetyl-CoA. Acetyl-CoA is also formed from pyruvate decarboxylation, in which CoA participates with thiamine pyrophosphate and lipoic acid, two other important coenzymes. Thiamine pyrophosphate is the actual decarboxylating coenzyme that functions with lipoic acid to form acetyidihydrolipoic acid from pyruvate decarboxylation. CoA then accepts the acetyl group from acetyidihydrolipoic acid to form acetyl-CoA. Acetyl-CoA is an acetyl donor in many processes and is the precursor in important biosyntheses (e.g.. those of fatty acids, steroids, porphyrins, and acetylcholine). 

The unique function of lipoic acid is in the oxidation of the thiamin-bound active aldehyde (Fig. 15-15) in such a way that when the complex with thiamin breaks up, the acyl group formed by the oxidative decarboxylation of the oxoacid is attached to the... 

E2 is a catalytic activity found in the pyruvate dehydrogenase complex. It forms the core of the complex. 24 copies of E2 are found in the complex isolated from Azotobacter. E2 is covalently bound to lipoic acid, forming lipoamide. Lipoamide functions to oxidize the aldehyde moiety transferred to it from El to an acetyl group and to subsequently transfer it to coenzyme A, forming acetyl-CoA. 

Nawa et al, 1960) [Eq. (1)]. This reaction played an important role in elucidation of the nature of the functional form of lipoic acid (see Section III, A, 5). 

Fkj. 6. Functional form of lipoic acid in Escherichia coli pyruvate and -koto-glutarate dehydrogenation complexes. The earboxyl group of lipoie acid is bound in amide linkage to the e-amino group of a lysine residue, providing a flexible arm of approximately 14 A for the reactive dithiolane ring. 

Thiol group, sulfkydryl group, metcapto gro -SH, the functional group of thiols (mercaptans), i.e. the functional group of RSH, where R is the remainder of the molecule. T.g. may be structurally important as in Thiol enzymes (see), or functionally important as in Coenzyme A (see), Pantetheine-4 -phosphate (see), Lipoic acid (see), Thioredoxin (see), etc. The functional form of lipoic and thioredoxin is a dithiol. 

Lipoic acid presumably functions only when acyl generation and transfer occur and not in decarboxylation or aceton formation. The mechanism of acyl generation suggested in reaction 2, Fig. 4, is the carbanion cleavage of the disulfide bond to form the free thioester wuth CoA and the free sulfhydryl of lipoic acid. 

The function of the amino group in TPP is, therefore, still an open question. However Reed and De Busk suggest that a-lipoic acid is connected to thiamine through a peptidic linkage between the carboxyl of a-lipoic acid and the amino group of thiamine to form lipothiamide. This finding would account for the essential nature of the amino group as far as oxidative decarboxylation is concerned. 

In view of the fact that lipoic acid is a cyclic disulfide, it is tempting to speculate on its function as a 2-carbon carrier in pyruvate oxidation through a thioester in a fashion similar to the CoA fimction in this reaction. Similarly the disulfide nature of this factor invites speculation on its possible role as an oxidation-reduction coenzyme by going through a sulfhydryl form. It is a curious fact that three of the factors involved in pyruvate oxidation, thiamine pyrophosphate, CoA, and POF, all contain sulfur. In the first two of these factors, the sulfur appears to play an important role in their mechanism of action. By analogy one would suppose that the disulfide grouping of POF will be prominent in its mechanism of action. 

This research has been one of the well-kept secrets of the 1940-45 war. Lewisite (a powerful vesicant not used on the battlefield) is. in contact with water, activated to the arsenoxide which has a great afiOnity for SH groups of proteins, enzymes and coenzymes and particularly for thioctic acid (or a-lipoic add). This, in its reduced form, has two closely located thiol functions. 

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