Lipoic acid chemistry

In connection with lipoic acid chemistry, mention should be made of arsenic compounds, some of the oldest and best-known poisons used throughout history. More recently, organic derivatives have been used as fungicides and insecticides. The more important arsenic compounds from a toxic stand point are trivalent compounds. Arsenite (0=As — O ) for instance is noted for its tendency to react rapidly with thiol groups, especially dithiols such as reduced lipoic acid. The result is that by blocking oxidative enzymes which require lipoic acid, arsenite causes the accumulation of pyruvate and other a-keto acids. 

The mechanism of the pyruvate dehydrogenase reaction is a tour de force of mechanistic chemistry, involving as it does a total of three enzymes (a) and five different coenzymes—thiamine pyrophosphate, lipoic acid, coenzyme A, FAD, and NAD (b). 

The reaction of hydroxyethyl-TPP with the oxidized form of lipoic acid yields the energy-rich thiol ester of reduced lipoic acid and results in oxidation of the hydroxyl-carbon of the two-carbon substrate unit (c). This is followed by nucleophilic attack by coenzyme A on the carbonyl-carbon (a characteristic feature of CoA chemistry). The result is transfer of the acetyl group from lipoic acid to CoA. The subsequent oxidation of lipoic acid is catalyzed by the FAD-dependent dihydrolipoyl dehydrogenase and NAD is reduced. 

There are two 2-oxoacid dehydrogenase multienzyme complexes in E. coli. One is specific for pyruvate, the other for 2-oxoglutarate. Each complex is about the size of a ribosome, about 300 A across. The pyruvate dehydrogenase is composed of three types of polypeptide chains El, the pyruvate decarboxylase (an a2 dimer of Mr — 2 X 100 000) E2, lipoate acetyltransferase (Mr = 80 000) and E3, lipoamide dehydrogenase (an a2 dimer of Mr = 2 X 56 000). These catalyze the oxidative decarboxylation of pyruvate via reactions 1.6, 1.7, and 1.8. (The relevant chemistry of the reactions of thiamine pyrophosphate [TPP], hydroxyethylthiamine pyrophosphate [HETPPJ, and lipoic acid [lip-S2] is discussed in detail in Chapter 2, section C3.)... 

Combination of microbiological chemistry, often yielding scaffolds not easily obtained by purely chemical means, and combinatorial chemistry, enabling rapid and efficient synthesis of analogs, provides a valuable tool for generation of novel test compounds. As an example [24] we describe here the application of our lipoic acid-derived thioketal linker [25] to the solid-phase synthesis of A4-3-keto steroidal ureas from / -sitosterol. 

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

Other redox reagents include dinucleotides such as FAD (flavine adenine dinucleotide), lipoic acid, which we will meet when we discuss the chemistry of thiamine, and ascorbic acid (vitamin C)> which you met in Chapter 49. Ascorbic acid can form a stable enolate anion that can transfer a hydride ion to a suitable oxidant. 

Heterocycles of this type occur widely. The benzo[l,3]dioxole ring system is often found in natural products and their degradation products, e.g., sesamol 38 lipoic acid 39 is a naturally occurring 1,2-dithiolane derivative. The 1,3-dithiolanes 40 are commonly known as 1,3-dithioacetals and have been extensively used in carbonyl group chemistry. In the absence of cyclic conjugation, ring sulfur atoms can readily exist in higher oxidation states as, for example, in the oxathiole S, -dioxide 41. 1,3,2-Dioxathiolane A-oxides 42 (cyclic sulfites) and 1,3,2-dioxathiolane A,A-dioxides (cyclic sulfates) are useful as synthetic equivalents of epoxides. 

Desulfurization of a number of thiols and disulfides, including the lipoic acid amide 174 under visible light irradiation, has received attention because of mild reaction conditions and the possibility to apply the same method in peptide chemistry (Scheme 23) <1999TA2643>. Accordingly, thioctic amide 174, that is, 5-(l,2-dithiolan-3-yl)pen-tanamide, was photochemically desulfurized in 36h in a one-pot reaction, giving 1-octanamide 175 in good yield. 

The RSH/RSSR interconversion is well known in organic chemistry due to its biological importance in systems like cysteine-cystine, glutathione and the corresponding disulfide, and Q -lipoic acid and related dithiol. 

This looks like a simple reaction based on very small molecules. But look again. It Is a very strange reaction indeed. The molecule of CO2 clearly comes from the carboxyl group of pyruvate, but how is the C-C bond cleaved, and how does acetyl CoA Join on If you try to draw a mechanism you will see that there must be more to this reaction than meets the eye. The extra features are two new cofactors, thiamine pyrophosphate and lipoic acid, and the reaction takes place in several stages with some interesting chemistry involved. 

Even though E. coli is a very well-studied bacterium, many interesting mechanistic problems in cofactor biosynthesis in this organism remain unsolved. The mechanisms for the formation of the nicotinamide ring of NAD, the pyridine ring of pyridoxal, the pterin system of molybdopterin, and the thiazole and pyrimidine rings of thiamin are unknown. The sulfur transfer chemistry involved in the biosynthesis of lipoic acid, biotin, thiamin and molybdopterin is not yet understood. The formation of the isopentenylpyrophosphate precursor to the prenyl side chain of ubiquinone and menaquinone does not occur by the mevalonate pathway. None of the enzymes involved in this alternative terpene biosynthetic pathway have been characterized. The aim of this review is to focus attention on these unsolved mechanistic problems. 

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. 

The chemistry of the cofactors has provided a fertile area of overlap between organic chemistry and biochemistry, and the organic chemistry of the cofactors is now a thoroughly studied area. In contrast, the chemistry of cofactor biosynthesis is still relatively underdeveloped. In this review the biosynthesis of nicotinamide adenine dinucleotide, riboflavin, folate, molyb-dopterin, thiamin, biotin, lipoic acid, pantothenic acid, coenzyme A, S-adenosylmethionine, pyridoxal phosphate, ubiquinone and menaquinone in E. coli will be described with a focus on unsolved mechanistic problems. 

G. P. Biewenga G. R. M. M. Haenen A. Bast, An Overview of Lipoate Chemistry. In Lipoic Acid in Health and Disease J. Fuchs,... 

Reed, L.J. The chemistry and function of lipoic acid. Advanc. Enzymol. 18, 319-347(1957)... 

Schmidt, U., Altland, K., Goedde, H.W. Biochemistry and chemistry of lipoic acids. Advanc. Enzymol. 32, 423-469 (1969)... 

In several areas of chemistry, the success or failure of an investigation can depend on the ability of a chemist to isolate tiny quantities of crystalline substances. Often the compounds of interest must be extracted from enormous amounts of extraneous material. In one of the more spectacular examples, Reed et al. isolated 30 mg of the crystaUine coenzyme lipoic acid from 10 tons of beef Uver residue. ... 

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