Biosynthesis of Thyroxine

In 1939, von Mutzenbecher showed that, if diiodotyrosine was incubated at an alkaline pH under aerobic conditions, small amounts of thyroxine were formed. This work gave the first direct experimental evidence that the reaction postulated by Harington could take place. Later, with the aid of radioactive iodine it was shown by the studies of Chaikoff and of Leblond and their collaborators that this reaction does indeed take place and it is now generally accepted that diiodotyrosine is the precursor of thyroxine in the thyroid. The large amount of experimental work which has contributed to this knowledge has recently been reviewed (Roche and Michel, 1951 Albert, 1952 Gross and Pitt-Rivers, 1952c) and will not now be considered in detail. Instead we will consider the means whereby the reaction is achieved in the body. 

The iodination of tyrosine itself in the thyroid probably requires no enzymic catalysis substitution of iodine in the phenolic nucleus of tyrosine is a reaction which takes place rapidly at the pH of body tissues, and it seems an unnecessary elaboration to assume enzymic intervention. Substitution occurs in two stages, giving monoiodotyrosine and diiodotyrosine. Monoiodotyrosine was first detected in the thyroid by Fink and Fink (1948), and since then its presence has been confirmed by many other workers. Monoiodotyrosine is physiologically inactive and was at first regarded merely as the precursor of diiodot3rrosine it may, however, have a more important place in thyroid biochemistry this will be discussed later. 

The coupling of two molecules of diiodotyrosine to give one molecule of thyroxine leads to the over-all loss of one alanine side chain, but the form in which this 3-carbon residue is removed is still not yet determined. Up till now, no work has been done on this reaction in the thyroid itself or in isolated thyroid tissues. All the evidence comes from in vitro incubations of diiodotyrosine or its derivatives modelled on von Mutzenbecher s experiments. Johnson and Tewkesbury (1942) found that after such incubations pyruvic acid and ammonia could be detected in the reaction mixture Ohno (see Roche and Michel, 1951) with the aid of chromatography was able to detect serine. Both of these compounds are likely results of the reaction, but at present neither of them has been confirmed. Experiments are still in progress (Pitt-Rivers, unpubhshed) to determine the nature of the alanine residue obtained during aerobic incuba tion of diiodotyrosine or its derivatives. It must, however, be emphasized that even if the nature of this residue were established in in vitro experiments, it would still be necessary to demonstrate that the same reaction takes place in the thyroid gland itself. 

We have seen that the coupling of diiodotyrosine to give thyroxine can occur in vitro to a small extent. However, the protection of both the amino and carboxyl groups of diiodotyrosine leads to the formation 

Before leaving the subject of the iodination of amino acids in the thyroid gland, it may be of interest to mention the presence of mono-iodohistidine, discovered by Roche, Lissitzky, and Michel (1961) in labeled rat thyroglobulin hydrolyzates. This amino acid is present only in small amounts and might be considered as a chemical accident, merely resulting from the ease in which histidine can be iodinated. This reaction has been studied in vitro by Roche, Lissitzky, Michel, and Michel (1951) the iodination of histidine is considerably slower than that of tyrosine. 

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Tyrosine gives rise to a variety of hormones, neurotransmitters, and other nitrogenous substances. The biosynthesis of thyroxine and the catecholamines was described in Chapter 16. In the melanoblasts, tyrosine gives rise to melanins, which are pigments of the eyes, skin, and hair ... 

After Enrico Fermi (Fig. 6.24) had described in 1934 the first radioactive isotope of iodine, 1, it became possible to explore the biosynthesis of thyroxine. For the first time, radioiodine enabled as a theranostic agent the diagnosis of thyroid cancer by autoradiography and also its radiologic treatment (Fig. 6.25). 

Biochemical iodination, as in the biosynthesis of thyroxine, occurs with enzymatic catalysis. 

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.]... 

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 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. 

Electrophilic aromatic halogenations occur in the biosynthesis of numerous naturally occurring molecules, particularly those produced by marine organisms. In humans, the best-known example occurs in the thyroid gland during the biosynthesis of thyroxine, a thyroid hormone involved in regulating growth and metabolism. The amino acid tyrosine is first iodinated by thyroid peroxidase, and two of the iodinated tyrosine molecules then couple. The... 

Figure 4.15. Some model reactions for the biosynthesis of thyroxine ...

In 1956, Hillman suggested that the tirst step in the formation of thyroxine from di-iodo-L-tyrosine (75) might be the deamination of the ammo acid to its keto analogue (81), and later work has shown that the oxidative coupling of (75) and (81) is an efficient non-enzymic model for the biosynthesis of thyroxine The... 

For the biosynthesis of thyroxine compare Chapt. XX-4 the steps in the formation of epinephrine are discussed in Chapt. XX-5. 

Thymine, electrostatic potential map of, 1104 structure of, 1101 Thyroxine, biosynthesis of, 551 structure of. 1020 TIme-of-flight (TOP) mass spectrometry, 417-418 Titration curve, alanine, 1023 TMS, see Tetramethylsilane see Trimethylsilyl ether Tollens reagent, 701 Tollens test, 992... 

Oza VB, Salamonczyk GM, Guo Z, Sih CJ (1997) Model Reactions of Thyroxine Biosynthesis. Identification of the Key Intermediates in Thyroxine Formation from 3,5-Diiodo-L-tyrosine and 4-FIydroxy-3,5-diiodophenylpyruvic Acid. J Am Chem Soc 119 11315... 

Fatty add synthetase is not controlled directly by phosphorylation however, insulin, glucagon, and thyroxine have an effect on its activity by controlling its cellular concentration. Both insulin and thyroxine increase the biosynthesis of the enzyme, whereas glucagon is inhibitory. Thyroxine and glucagon appear to regulate the biosynthesis at the transcription level, whereas insulin affects the enzyme activity at the translation level. It has no effect on cellular fatty add synthetase mRNA concentration. In summary, fatty add synthetase levels are up in the fed state and down in the fasting state. 

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

Phenylketonuria (PKU) is an inborn error of metabolism by which the body is unable to convert surplus phenylalanine (PA) to tyrosine for use in the biosynthesis of, for example, thyroxine, adrenaline and noradrenaline. This results from a deficiency in the liver enzyme phenylalanine 4-mono-oxygenase (phenylalanine hydroxylase). A secondary metabolic pathway comes into play in which there is a transamination reaction between PA and a-keto-glutaric acid to produce phenylpyruvic acid (PPVA), a ketone and glutamic acid. Overall, PKU may be defined as a genetic defect in PA metabolism such that there are elevated levels of both PA and PPVA in blood and excessive excretion of PPVA (Fig. 25.7). 

There are three plausible pathways for the biosynthesis of triiodothyronine. It could be formed from one molecule each of mono- and diiodotyrosine in the same way as thyroxine can be formed from two molecules of diiodotyrosine or it could be formed by incomplete iodination of preformed thryonine or diiodothyronine or it could be formed by deiodina-tion of thyroxine. Formation by deiodination is favored by English work-... 

Figure 45-2. Biosynthesis of the thyroid hormones Tj and in the thyroid follicular cell and release into the bloodstream. Abbreviations are as follows TG, thyroglobulin MIT, monoiodotyrosine DIT, diiodotyrosine Tj, triiodothyronine T., thyroxine.

Fig. 1. Schematic representation of the pathways of the biosynthesis of the thyroid hormones. The sites of biosynthetic defects are also indicated. [L] = active iodide," MIT = monoiodotyrosine, DIT = diiodotyrosine, Ts — triiodothyronine, T = thyroxine, TBP = thyroid hormone-binding proteins.

With regard to the biosynthesis of triiodothyronine, two pathways are possible (1) enzymic reduction of one iodine atom from thyroxine, and (2) the coupling of one molecule of monoiodotyrosine with one molecule of diiodotyrosine. These alternative pathways are shown in the following diagram ... 

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