Lipoic acid reduction

Planchard A., Mignot L. and Junter G.A. (1988) Microbial sensor based on lipoic acid reduction. Sensors Actuators, 14, 9-17. 

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. 

The special properties of lipoic acid arise from the ring strain experienced by oxidized lipoic acid. The closed ring form is approximately 20 kj higher in energy than the open-chain form, and this results in a strong negative reduction potential of about —0.30 V. The oxidized form readily oxidizes cyanides to isothiocyanates and sulfhydryl groups to mixed disulfides. 

Ribonucleotide reductase differs from the other 5 -deoxyadenosyl-cobalamin requiring enzymes in a number of respects. Hydrogen is transferred from coenzyme to the C2-position of the ribose moiety without inversion of configuration. Also since lipoic acid functions in hydrogen transfer, exchange with solvent protons takes place. Furthermore, exchange between free and bound 5 -deoxyadenosylcobalamin occurs rapidly during catalysis. Evidence for a Co(I)-corrin as an intermediate for this reduction is presented in our section on electron spin resonance. 

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). 

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. 

Another result of the ring strain is that the reduction potential E° (pH 7, 25°C), is -0.30 V, almost the same as that of reduced NAD (-0.32V). Thus, reoxidation of reduced lipoic acid amide by NAD+ is thermodynamically feasible. Yet another property attributed to the ring strain in lipoic acid is the presence of an absorption maximum at 333 nm. 

In the first step of the conversion catalyzed by pyruvate decarboxylase, a carbon atom from thiamine pyrophosphate adds to the carbonyl carbon of pyruvate. Decarboxylation produces the key reactive intermediate, hydroxyethyl thiamine pyrophosphate (HETPP). As shown in figure 13.5, the ionized ylid form of HETPP is resonance-stabilized by the existence of a form without charge separation. The next enzyme, dihydrolipoyltransacetylase, catalyzes the transfer of the two-carbon moiety to lipoic acid. A nucleophilic attack by HETPP on the sulfur atom attached to carbon 8 of oxidized lipoic acid displaces the electrons of the disulfide bond to the sulfur atom attached to carbon 6. The sulfur then picks up a proton from the environment as shown in figure 13.5. This simple displacement reaction is also an oxidation-reduction reaction, in which the attacking carbon atom is oxidized from the aldehyde level in HETPP to the carboxyl level in the lipoic acid derivative. The oxidized (disulfide) form of lipoic acid is converted to the reduced (mer-capto) form. The fact that the two-carbon moiety has become an acyl group is shown more clearly after dissocia-... 

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. 

Chen F, Ye J, Zhang X, et al. 1997. One-electron reduction of chromium(VI) by a-Lipoic acid and related hydroxyl radical generation, dG hydroxylation and nuclear transcription factor-KB activation. Arch Biochem Biophys 338(2) 165-172. 

Componnds that contain arsenic in general are carcinogenic. This is probably the resnlt of its reduction to arsenic . The thiophilicity of arsenic affect key enzymes, such as acetylcholine estereases, lipoic acid, and hemoglobin. Long-term contact with the organometallic forms cause hyperactivity, dizziness, speech, and psychological problems, possibly linked to methylation which in turn facilitates its transport across the blood-brain barrier. ... 

The mechanisms of biomethylation of arsenic have not been documented. However, Cullen and coworkers have proposed a plausible mechanistic model based on oxidative methylation of arsenic(III) by S-adenosylmethionine and reduction by a thiol such as lipoic acid. 

Lipoic acid (thioctic acid) functions as an intermediate in the oxidation-reduction reaction of the oxidative decarboxylation of certain ketoacids. 

Howie, J.K., Houts, J.J., and Sawyer, D.T. 1977. Oxidation-reduction chemistry of DL-a-lipoic acid, propanedithiol, and trimethyllene disulfide in aprotic and in aqueous media. Journal of the American Chemical Society 99, 6323-6326. 

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