Lexicon #4 - Lipoic Acid

Lipoic Acid

Lipoic acid also known as $\alpha$-lipoic acid or thioctic acid, is synthesized in the body by the enzyme lipoyl synthase. As a result of the mechanism of this enzyme, lipoic acid is synthesized attached to proteins. No free lipoic acid is produced in the body. Refer to this Wikipedia page for more details on the enzyme’s mechanism of action.

Structure

The structure of lipoamide looks rather complex on first glance however, the region of the molecule involved in the chemistry is simple (highlighted region). Lipoamide is a redox cofactor, that is, it toggles between the oxidized and reduced state in the body. In the oxidized state, lipoamide contains an $S-S$ bond. During its reduction, this bond is cleaved and two protons along with two electrons are added to give rise to dihydrolipoamide (reduced form).

Reactions

Enzyme complexes of the 2 ketoacid family:
 - Pyruvate dehydrogenase complex
 - Alpha ketoglutarate dehydrogenase complex
 - Branched-chain alpha keto acid dehydrogenase complex

2 Ketoacid enzyme complexes (also known as $\alpha$-ketoacid enzyme complexes) require lipoic acid as a cofactor. A general outline of lipoamide mechanism is as follows. Let the enzyme using lipoamide as a cofactor be $E_2$. During the reaction, a metabolite reduces lipoamide to dihydrolipoamide. Dihydrolipoamide is then transferred to the subsequent enzyme in the complex ($E_3$ in the figure below). This enzyme contains an $S-S$ linkage along with a covalently bound FAD. Simultaneously, dihydrolipoamide is oxidized and the $S-S$ linkage of the enzyme is reduced. Thus, lipoamide is reformed and can be used again for catalysis. The covalently bound FAD re-oxidizes the enzyme to which it is covalently attached ($E_3$ in the figure below).

Scheele’s green

Arsenic (As) has been known to be a poison since ancient times. As($\rm III$) compounds, such as arsenite and organic arsenicals, are toxic because of their ability to covalently bind sulfhydryl compounds. This is particularly true of vicinal (adjacent) sulfhydryls such as those of lipoamide because they can form bidentate adducts.

Arsenic compounds are poisonous because they sequester lipoamide thus inhibiting enzymes (such as 2-ketoacid dehydrogenases) that require lipoamide as a cofactor.

Throughout history there have been instances of accidental arsenic poisoning. Scheele’s Green, chemically a cupric arsenite was used as a color for paper and to dye cotton and linen back when the toxicity of arsenic compounds was not readily known. Nineteenth-century journals contained reports of children wasting away in bright green rooms, of ladies in green dresses swooning and newspaper printers being overcome by arsenic vapors. There is one example of an acute poisoning of children attending a Christmas party where dyed candles were burned. Moreover, Charles Darwin and Napoleon are thought to have died of arsenic poisoning.

Sources

• Thumbnail: Scheele’s green (clothing) causes death.
• Scheele’s green Wikipedia article
• Charles Darwin’s health Wikipedia article
• Biochemistry a textbook by Donald Voet and Judith G. Voet