Incorporation in Thyroxine Biosynthesis

Electrophilic aromatic substitution also plays a role in the 1927 laboratory synthesis of thyroxine by C. Harington and G. Barger. Their synthesis helped prove the structure of this important hormone by comparison of the synthetic material with natural thyroxine. Harington and Barger used electrophilic aromatic substitution to introduce the iodine atoms at the ortho positions in the phenol ring of thyroxine. They used a different reaction, however, to introduce the iodine atoms in the other ring of thyroxine (nucleophilic aromatic substitution—a reaction we shall study in Chapter 21.) 

The remainder of the thyroglobin protein is indicated by the shaded area.) 

The biosynthesis of thyroxine in the thyroid gland through the iodination, rearrangement, and hydrolysis (proteolysis) of thyroglobin Tyr residues. The relatively scarce r is actively sequestered by the thyroid gland. 

Hydrogen abstraction from the methyl group of methylbenzene (toluene) produces a radical called the benzyl radical  

The name benzyl radical is used as a specific name for the radical produced in this reaction. The general name benzylic radical applies to all radicals that have an unpaired electron on the side-chain carbon atom that is directly attached to the benzene ring. The hydrogen atoms of the carbon atom directly attached to the benzene ring are called benzylic hydrogen atoms. A group bonded at a benzylic position is called a benzylic substituent. 

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Thyroxine (see the model above ) is an aromatic compound and a key hormone that raises metabolic rate. Low levels of thyroxine (hypothyroidism) can lead to obesity, lethargy, and an enlarged thyroid gland (goiter). The thyroid gland makes thyroxine from iodine and tyrosine, which are two essential components of our diet. Most of us obtain iodine from iodized salt, but iodine is also found in products derived from seaweed, like the kelp shown above. An abnormal level of thyroxine is a relatively common malady, however. Fortunately, low levels of thyroxine are easily corrected by hormone supplements. After we study a new class of reaction in this chapter called electrophilic aromatic substitution, we shall return to see how that reaction is related to thyroxine in "The Chemistry of... Iodine Incorporation in Thyroxine Biosynthesis."... 

Biochemical iodination, as in the biosynthesis of thyroxine, occurs with enzymatic catalysis. Thyroxine biosynthesis is discussed further in The Chemistry of. .. Iodine Incorporation in Thyroxine Biosynthesis box in Section 15.1 IE. 

The relevance of the results obtained in vitro, in either liver slices or perfusates, to the general problem of lipoprotein biosynthesis in the intact animal remains to be established. In vivo synthesis of the protein moiety of serum 3-lipoprotein was studied in roosters by administration of S -methionine (Florsheim et al., 1963), followed by measurements of specific radioactivity of plasma 3-lipoprotein separated by dextran sulfate. Under these experimental conditions, enhancement of methionine incorporation was noted after pharmacological doses of ethanol, estrogens, and triiodothyronine. No significant effect was obtained after administration of epinephrine, cortisone, and thyroxine preparations. 

A noteworthy example of electrophilic aromatic substitution in nature, as mentioned in the introduction, is biosynthesis of the thyroid hormone thyroxine, where iodine is incorporated into benzene rings that are derived from tyrosine. 

Many studies have revealed that thyroid hormones markedly affect lipid metabolism in man and in several species of animals. Concerning fatty acid biosynthesis it was demonstrated that the administration of thyroxine stimulates the incorporation of l-l c acetate into fatty acids in rats and mice (Dayton et al, I960) (Gompertz and Greenbaum, 1966) (March and Mayer, 1959). According to Gompertz and Greenbaum (1966) these observations appear to be associated with an increase of stearyl-CoA desaturase activity. Moreover Myant and Iliffe (1963) found that rats treated with thyroxine showed an inhibition of acetate incorporation, but not of malonate incorporation, into fatty acids by mitochondria free, subcellular liver preparations. Other authors have shown that the thyrotoxic state was accompanied by an increased incorporation of acetyl-CoA to fatty acid and a rise in the activity of fatty acid synthetase in rat livers (Diamant et al, 1972) (Roncari and Murthy, 1975). However, in vitro studies of fatty acid synthesis in which liver supernatant of 105,000 xg and microsomal preparations were incubated with the hormone showed that thyroxine inhibits de novo synthesis of palmitate and stimulates the desaturation reactions (Faas et al, 1972). 

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