Thyroxine, biosynthesis

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... 

Since this process is involved in thyroxine biosynthesis,14 it is likely that the enzymic oxygenation also involves dioxetanes. The horseradish peroxidase (HRP)-catalyzed oxygenation of indole-3-acetic acid (53) affords electronically excited indole-3-aldehyde (54).83b The a-peroxylactone (2j) was postulated to be responsible for the feeble light... 

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. 

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. 

In this chapter we will first briefly describe the major parameters controlling the level of thyroid hormone production and its concentration by the target cell (see Ref. 6), i.e., biosynthesis and output from the thyroid gland, transport in the blood, conversion of the prohormone thyroxine (T4), to the active form, 3,5,3 -triiodo-... 

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. 

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 ... 

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.

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