Lipoic acid metabolism

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. 

Lipoic acid metabolism LipT - iipoate transporter Folate biosynthesis FolT/EcfAAT - folate transporter... 

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. 

University of Illinois, isolated Just 30 mg of lipoic acid from approximately 10 tons of liver No evidence exists of a dietary lipoic acid requirement by humans stricdy speaking, it is not considered a vitamin. Nevertheless, it is an essential component of several enzymes of intermediary metabolism and is present in body tissues in small amounts. 

Aerobic living features metabolize sugars and fatty acids to carbon dioxide. Accordingly, there are some kinds of decarboxylation reactions. TPP-mediated decarboxylation of pyruvic acid to acetaldehyde is one of the most important steps of the metabolism of sugar compounds (Fig. 1). When the intermediate reacts with lipoic acid instead of a proton, pyruvic acid is converted to acetylcoenzyme A, which is introduced to TCA cycle (Fig. 2). 

Group-transfer reactions often involve vitamins3, which humans need to have in then-diet, since we are incapable of realizing their synthesis. These include nicotinamide (derived from the vitamin nicotinic acid) and riboflavin (vitamin B2) derivatives, required for electron transfer reactions, biotin for the transfer of C02, pantothenate for acyl group transfer, thiamine (vitamin as thiamine pyrophosphate) for transfer of aldehyde groups and folic acid (as tetrahydrofolate) for exchange of one-carbon fragments. Lipoic acid (not a vitamin) is both an acyl and an electron carrier. In addition, vitamins such as pyridoxine (vitamin B6, as pyridoxal phosphate), vitamin B12 and vitamin C (ascorbic acid) participate as cofactors in an important number of metabolic reactions. 

The answer is A. This patient exhibits several signs of acute arsenic exposure, including the cholera-like gastrointestinal symptoms and probable dehydration. He may currently be in hypovolemic shock and beginning chelation therapy is the only recourse. Arsenic is a metabolic toxin because it inhibits enzymes that require lipoic acid as a coenzyme the PDH complex, the a-ketoglutarate dehydrogenase complex, and trans-ketolase of the pentose phosphate pathway. 

The oxidative cleavage of an a-oxoacid is a major step in the metabolism of carbohydrates and of amino acids and is also a step in the citric acid cycle. In many bacteria and in eukaryotes the process depends upon both thiamin diphosphate and lipoic acid. The oxoacid anion is cleaved to form C02 and the remaining acyl group is combined with coenzyme A (Eq. 15-33). 

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... 

Packer L., Tritschler H. J., and Wessel K. (1997). Neuroprotection by the metabolic antioxidant a-lipoic acid. Free Radic. Biol. Med. 22 359-378. 

The involvement of oxidative stress in AD has opened a new door for potential therapeutic targets. In this regard, several antioxidants are currently in clinical trials such as Idebenone, a-Lipoic acid, acetyl-L-carnitine (ALC), vitamin E, vitamin C, flavonoids, P-carotene, gingko biloba, and metal-chelating agents. Idebenone is a metabolic antioxidant and is normally synthesized as part of the mitochondrial oxidative phosphorylation system. Improvements in clinical status after treatment with idebenone have been shown in a dose-dependent manner compared to placebo and tacrine (Thai et al., 2003). 

In addition, CS reacts with the disulfhydryl form of lipoic acid, a coenzyme in the pyravate decarboxylase system (Olajos and Salem, 2001). Alteration in dihydrolipoic acid biochemistry can lead to decreased acetyl CoA levels, resulting in cellular injury. Therefore, tissue injury seems to be related to inactivation of these metabolic enzyme systems. The damage is transient because the enzymes can be rapidly reactivated if exposure is terminated (Beswick, 1983). 

Similarly, the coupling of LA to arylthiophene imidamide derivative 355, via a carboxamide linker, led to lipoic acid analogue 354, acting as a metabolic antioxidant and a nitric oxide synthase (NOS) inhibitor as well <2002BMCL1439>. 

The trivalent forms of arsenic apparently exerts their toxic effects chiefly by reacting with the sulfhydryl groups of vital cellular enzymes. Pyruvate dehydrogenase seems to be a particularly vulnerable site in the metabolism, because it contains the thiol lipoic acid that is especially reactive with trivalent arsenicals. 

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. 

Conlon BJ, Aran JM, Erre JP, Smith DW. Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant alpha-lipoic acid. Hear Res 1999 128 (l-2) 40-4. 

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). 

Thiamine pyrophosphate has two important coenzyme roles, both of which focus mostly on carbohydrate metabolism (Figs. 8.26 and 8.27). The active portion of the coen- rae is the thiazole ring. The first step in the oxidative decarboxylation of a-keto acids requires TPP. The two most common examples are pyruvate and a-ketoglutarate, oxidatively decarboxyatedto acetyl CoA and succinyl CoA, respectively. The same reaction is found in the metabolism of the branched-chain amino acids valine, isoleucine, leucine, and methionine. In all cases, TPP is a coenzyme in a mitochondrial multienzyme complex, consisting of TPP, lipoic acid, coenzyme A, FAD, and NAD. Note the number of vitamins required for the oxidative decarboxylation of a-keto acids thiamine (TPP), pantothenic acid (coenzyme A), riboflavin (FAD),and niacin (NAD). 

Lipoic acid is a vitally important antioxidant that also aids in the recycling of other antioxidants, especially vitamins C and E, coenzyme QIO, and glutathione. While it is found in meats and potatoes, adequate amounts are unlikely to be provided via food sources. Lipoic acid as a supplement helps to prevent oxidative damage associated with aging, disease, and metabolism. 

Obrosova IG, Cao X, Green DA, Stevens MJ. Diabetes-induced changes in lens antioxidant status, glucose utilization and energy metabolism effect of DL-alpha-lipoic acid. Diabetologia 1998 41 1442-1450. 

Chlorine, phosgene. Lewisite, and SM all react with thiol groups as well as produce oxidants. The arsenic group in Lewisite has a high affinity to the alpha and gamma thiol groups of lipoic acid found in enzymes (e.g., pyruvate oxidase). Oxidants occur as part of the normal metabolism of cells (redox homeostasis). In the diseased state (e.g., exposure to a chemical agent), there is an acute... 

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