Lipoic acid structure

Lipoic acid exists as a mixture of two structures a closed-ring disulfide form and an open-chain reduced form (Figure 18.33). Oxidation-reduction cycles interconvert these two species. As is the case for biotin, lipoic acid does not often occur free in nature, but rather is covalently attached in amide linkage with lysine residues on enzymes. The enzyme that catalyzes the formation of the lipoamide nk.2Lg c requires ATP and produces lipoamide-enzyme conjugates, AMP, and pyrophosphate as products of the reaction. 

FIGURE 18.33 The oxidized and reduced forms of lipoic acid and the structure of the lipoic acid-lysine conjugate. 

Chemical, biological, and pharmacological properties of lipoic acid as well as its therapeutic effects in several diseases (diabetes mellitus, liver cirrhosis, polyneuritis, etc.) are reviewed [198,199], It is evident from the chemical structures of LA and DHLA that only DHLA may be an efficient scavenger of all oxygen radicals, while LA should be active only in the reactions with highly reactive hydroxyl radicals. On the other hand, DHLA must be easily... 

In lipoic acid (6), an intramolecular disulfide bond functions as a redox-active structure. As a result of reduction, it is converted into the corresponding dithiol. As a prosthetic group, lipoic acid is usually covalently bound to a lysine residue (R) of the enzyme, and it is then referred to as lipoamide. Lipoamide is mainly involved in oxidative decarboxylation of 2-0X0 acids (see p. 134). The peptide coenzyme glutathione is a similar disulfide/ dithiol system (not shown see p. 284). 

An interesting synthetic approach to thietanes is the selective desulfurization of cyclic disulfides.The treatment of dithiolanes with a diethyl-aminophosphine results in a ring contraction to thietanes, (Eq. 19). This has been demonstrated with a-lipoic acid, a coenzyme with a dithiolane structure involved in the biological oxidation of pyruvic acid. The reaction is proposed to be initiated by the electrophilic attack of the phosphorus on the ring sulfur atom, resulting in the formation of an acyclic internal phosphonium salt, which by subsequent elimination of a phosphine sulfide, closes to the four-membered ring. °... 

Oxidative coenzymes with structures of precisely determined oxidation-reduction potential. Examples are NAD+, NADP+, FAD, and lipoic acid. They serve as carriers of hydrogen atoms or of... 

The reaction catalyzed by the first of these is illustrated in Table 15-2 (reaction type F). The other two enzymes usually promote the reverse type of reaction, the reduction of a disulfide to two SH groups by NADPH (Eq. 15-22). Glutathione reductase splits its substrate into two halves while reduction of the small 12-kDa protein thioredoxin (Box 15-C) simply opens a loop in its peptide chain. The reduction of lipoic acid opens the small disulfide-containing 5-membered ring in that molecule. Each of these flavoproteins also contains within its structure a reducible disulfide group that participates in catalysis. 

While Tetrahymena must have lipoic acid in its diet, we humans can make our own, and it is not considered a vitamin. Lipoic acid is present in tissues in extraordinarily small amounts. Its major function is to participate in the oxidative decarboxylation of a-oxoacids but it also plays an essential role in glycine catabolism in the human body as well as in plants.295 296 The structure is simple, and the functional group is clearly the cyclic disulfide which swings on the end of a long arm. Like biotin, which is also present in tissues in very small amounts, lipoic acid is bound in covalent amide linkage to lysine side chains in active sites of enzymes 2963... 

Phosphopantetheine, lipoic acid, and biotin, by virtue of their long, flexible structures, facilitate the physical translocation of chemically reactive species among separate catalytic sites. 

What structural features of biotin and lipoic acid allow these cofactors to be covalently bound to a specific protein in a multienzyme complex yet participate in reactions at active sites on other enzymes of the complex ... 

Polarography has been successfully applied to the investigation of structural problems involving sulphur compounds. The presence of a disulphide bond has been established by means of the polarographic reduction waves of cytochrome C (156) and lipoic acid (757), and in cyclic disulphides of the oxytocine and vasopressine type (158). The elucidation of the process responsible for the reduction wave of lipoic acid was carried out by comparison with reduction waves of cyclic disulphides, where the disulphide bond was incorporated into rings of various size. The similarity indicated that in lipoic acid an S—S bond which is a part of a larger cyclic system is reduced. 

Fig. 9.5 Chemical structures of low molecular weight antioxidants Melatonin (a) ascorbic acid (Vitamin C) (b) glutathione (c) lipoic acid (d) a-tocopherol (Vitamin E) (e) and a-tocotrienol (f)...

Copolymerization of lipoic acid (LPA) and 1,2-dithiane (DT) was also induced readily to give high polymers in high yields, and the resulting structure contained polycatenane structures [203]. The polymers revealed characteris-... 

Fig.8 Chemical structure of indole -lipoic acid derivatives [117]...

FIGURE 50.7. Lewisite, its structure and mechanism of action. Lewisite forms covalent bonds with lipoic acid, inactivating the en2yme pyruvate dehydrogenase (PDH). 

Due to the pendant carboxylic group, SAMs of lipoic acid have been used in a large number of surface modifications, providing access to new structure systems with potential applications in biotechnology and molecular electronics, etc. 

The function of this archaebacterial dihydrolipoamide dehydrogenase in the absence of its normal multienzyme complexes is unknown [42,43]. Detailed structural studies, beginning with current experiments to clone and sequence the gene [44], may throw light on this. Meanwhile, we have surveyed a number of archaebacterial genera for the presence of the enzyme [43] and have correlated this with the presence of lipoic acid. The data available are summarised in Table 1. 

No I all cofaclyrs are derived from vitamins, Coenzyme Q, lipoic acid, dolichol phosphate, biopterin, heme, and molybdopterin are cofactors that are synthesized in the body from simple organic compounds. Heme and molybdopterin are relatively complex, from a nutritional point of view, because they require metal ions as part of their structure. 

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). 

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