Thyroxine biosynthesis, mechanism

Ma Y-A, Sih CJ, Flarms A (1999) Enzymatic Mechanism of Thyroxine Biosynthesis. Identification of the Lost Three-Carbon Fragment . J Am Chem Soc 121 8967... 

Lithium carbonate is used in the treatment of manic depressive illnesses. The exact mechanism of its action is not known but it may interfere with cyclic-AMP mediated processes. The level of the drug in the blood must be monitored periodically as toxic reactions (tremors, diarrhoea, vomitting and drowsiness) can result from overdosage. Recently it has been found that lithium inhibits thyroxine biosynthesis and this may lead to hypothyroidism. 

Numerous L-tyrosine containing peptides and proteins may be utilised to synthesise thyroxine (80) by iodination and without enzymic mediation . Iodine reacts with the L-tyrosine residues in the peptide to form mono- and di-iodo-L-tyrosine residues. An oxidative coupling of two, appropriately placed, di-iodo-L-tyrosyl residues then occurs to give thyroxine (80). Considerable evidence has been accumulated to surest that thyroxine biosynthesis follows the same pathway in vivo, but other mechanisms have been suggested and examined . The exact role of the protein thyroglobulin in thyroxine biosynthesis is, however, not clear for although L-tyrosine residues of other proteins may be readily iodinated in vitro only thyroglobulin is known to make thyroxine in vivo. 

The structure of thyroxine, a thyroid hormone that helps to regulate metabolic rate, was determined in part by comparison with a synthetic compound believed to have the same structure as natural thyroxine. The final step in the laboratory synthesis of thyroxine by Harington and Barger, shown helow, involves an electrophilic aromatic substitution. Draw a detailed mechanism for this step and explain why the iodine substitutions occur ortho to the phenolic hydroxyl and not ortho to the oxygen of the aryl ether. [One reason iodine is required in our diet (e.g., in iodized salt) is for the biosynthesis of thyroxine.]... 

Thyroid hormones have long been known to affect lipid metabolism. Thyroxine undoubtedly controls cholesterol metabolism serum cholesterol levels are markedly increased in hypothyroidism and decreased in hyperthyroidism. There are various ways by which thyroxine could cause cholesterol to accumulate in blood direct stimulation of the pathway involved in cholesterol biosynthesis block of cholesterol use for further biosynthesis indirect stimulation of cholesterol synthesis by acceleration of pathways that provide precursors of coenzymes needed for cholesterol synthesis and indirect stimulation of cholesterol synthesis by blocking pathways that use those precursors involved in cholesterol synthesis. The exact mechanism by which thyroxine induces the accumulation of cholesterol in serum needs to be elucidated. The effect of thyroid hormones on blood cholesterol must be understood because hypothyroidism is known to enhance the development of experimental arteriosclerosis in animals. 

The mechanism by which the absence of the dehalogenase leads to low thyroxine levels and cretinism is not clear. Two different theories have been proposed. The first postulates the existence of an additional defect namely, an inability to couple iodotyrosine to form T3 and T4. The second proposes that the absence of dehalogenase leads to a glandular hyperfunction in which hormone precursors are released before they can be used for thyroglobulin biosynthesis. It has now been established that the dehalogenase defect results from the absence of a single autosomal recessive gene. 

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