Lipoic acid functions

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. 

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 telomer 40 is converted into lipoic acid (136) by modification of three functional groups, as shown[l 16]. 

Rapid and reversible making and breaking of the sulfur-sulfur bond is essential to the biological function of a lipoic acid... 

Lipoic acid is an acyl group carrier. It is found in pyruvate dehydrogenase zard a-ketoglutarate dehydrogenase, two multienzyme complexes involved in carbohydrate metabolism (Figure 18.34). Lipoie acid functions to couple acyl-group transfer and electron transfer during oxidation and decarboxylation of a-keto adds. 

The PDHC catalyzes the irreversible conversion of pyruvate to acetyl-CoA (Fig. 42-3) and is dependent on thiamine and lipoic acid as cofactors (see Ch. 35). The complex has five enzymes three subserving a catalytic function and two subserving a regulatory role. The catalytic components include PDH, El dihydrolipoyl trans-acetylase, E2 and dihydrolipoyl dehydrogenase, E3. The two regulatory enzymes include PDH-specific kinase and phospho-PDH-specific phosphatase. The multienzyme complex contains nine protein subunits, including... 

The clinical significance of thiamine and its necessity for pyruvic acid oxidation has been discussed. Recent reports concerning the coenzyme function of thiamine in pentose (H13), tryptophan (D2), and lipoic acid metabolism (R6) have increased our knowledge of thiamine in metabolism and lend added interest to the role of thiamine in clinical problems. This method has also been used to assay thiamine in liver and brain. 

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). 

The body s natural defenses against overenthusiastic oxidation include a-lipoic acid, reduced glutathione, ascorbic acid, the tocopherols, the carotenoids, and a number of enzymes such as epoxide hydrolase and the like. Very efficient DNA repair systems also operate defensively. These various means are remarkably effective, but DNA assault is continuous, cumulative, and implacable. Thus, many degenerative diseases are associated with aging because of the gradual slippage in functional fidelity of cellular machinery which occurs with age. 

Coenzymes The pyruvate dehydrogenase complex contains five coenzymes that act as carriers or oxidants for the intermediates of the reactions shown in Figure 9.3. Ei requires thiamine pyrophosphate, Ep requires lipoic acid and coenzyme A, and E3 requires FAD and NAD+. [Note Deficiencies of thiamine or niacin can cause serious central nervous system problems. This is because brain cells are unable to produce sufficient ATP (via the TCA cycle) for proper function if pyruvate dehydrogenase is inactive.]... 

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... 

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... 

In humans 100 or more years in age some mitochondrial mutations are associated with good health and longevity.541 Dietary factors doubtless play a role. For example, supplementation of rats diet with lipoic acid improved mitochondrial function and increased the metabolic rate of old animals.542... 

Coenzymes are molecules that act in cooperation with enzymes to catalyze biochemical processes, performing functions that enzymes are otherwise chemically not equipped to carry out. Most coenzymes are derivatives of the water-soluble vitamins, but a few, such as hemes, lipoic acid, and iron-sulfur clusters, are biosynthesized in the body. Each coenzyme plays a unique chemical role in the enzymatic processes of living cells. 

The absence in halobacteria of the oxoacid dehydrogenase complexes creates another puzzle. In most known systems, the role of the enzyme lipoamide dehydrogenase is to reoxidize the lipoic acid that is involved in the oxidation of the oxoacids in the oxoacid dehydrogenase complexes. This enzyme was nonetheless found in H. halobium and purified to homogeneity by Danson et al. (1986). What, then, is its function It is likely that lipoamide dehydrogenase assumes a different role in halobacteria. Another reducing system unique to... 

Some authors claim that liposaccharides can depress the content of TNF-a and increase the activity of superoxide dismutase (SOD) and catalase, thus—via mediators—they can affect the immune system (Can et al. 2003). It has been demonstrated that the NF-p transcription factor, (highly sensitive to the redox potential in its environment), which regulates synthesis of many mediators—cytokines, associated with inflammatory condition and the phenomenon of adhesion of cells— becomes deregulated in old age. Defense functions in such cases (and primarily in arthritis and arthritis-related conditions) are said to be performed by antioxidants (including a-lipoic acid), which can modulate the activity of monocytes and inhibit changes caused by deregulating of the transcription factor NF-kB under the influence of redox conditions in elderly people (Lee and Hughes 2002). 

According to Barnes and Stoner [8] dialkyltin (and -lead) compounds in mammalian systems are inhibitors of the enzymes o -keto acid oxidases by interference with the physiological function of a dithiol compound, the coenzyme -lipoic acid. The same mechanism may apply for the antimicrobial activity of these compounds. It remains, however, remarkable that their antifungal activity is rather low, whereas in particular... 

Gunsalus, I. C. The chemistry and function of the pyruvate oxidation factor (lipoic acid). J. Cellular Comp. Physiol. 41, Suppl. 1, 113—136 (1953). 

This new intermediate contains a new and strange C=C double bond. It has OH, N, and S substituents making it very electron-rich. As the nitrogen is the most electron-donating you can view it as an cnamine, and it attacks the disulfide functional group of lipoic acid, the other cofactor in the reaction. 

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