Thyroxine precursors

Thiouracil. 2,3-Dihydro-2-ihioxo-4(IH)-pyri-midinone 2-mercapto-4-hydroxypyrimidine 4-hydroxy -2( I ft) -pyrimidinethione 2 -mercapto -4( 1H) -py rimidinone 6 -hydroxy -2 -mercaptopyrimidine 2-mercapto-4. pyrimi -done Deracil. C4H4N,OS mol wt 128.15. C 37.49%, H 3.15%, O 12.48%, N 21.86%, S 25 02%. Occurs in seeds of Brassica, Cruciferae Purves, Brit. J. Exp. Pathol 22, 241 (1941). Prepd by condensing ethyl formylacetate with thiourea Wheeler. Liddle, 3m. Chem. J. 40, 550(1908). Antithyroid activity results from its interference with the iodina-tion of thyroxine precursors see Maloof, Soodak, Pharmacol. Rev. 15, 72-79 (1963). Inhibition of nucleic acid metabolism Cardeilhac, Proc, Soc. Exp. Biot Med. 125, 692 (1967). Toxicology K. K. Carroll, R. L, Noble, J. Pharmacol. Exp. Ther. 97, 478 (1949). 

Several amino acids are also the precursors of other compounds, eg, purines, pyrimidines, hormones such as epinephrine and thyroxine, and neurotransmitters. 

Neural cells convert tyrosine to epinephrine and norepinephrine (Figure 31—5). While dopa is also an intermediate in the formation of melanin, different enzymes hydroxylate tyrosine in melanocytes. Dopa decarboxylase, a pyridoxai phosphate-dependent enzyme, forms dopamine. Subsequent hydroxylation by dopamine P-oxidase then forms norepinephrine. In the adrenal medulla, phenylethanolamine-A -methyltransferase uti-hzes S-adenosyhnethionine to methylate the primary amine of norepinephrine, forming epinephrine (Figure 31-5). Tyrosine is also a precursor of triiodothyronine and thyroxine (Chapter 42). 

The formation of triiodothyronine (T3) and tetra-iodothyronine (thyroxine T4) (see Figure 42—2) illustrates many of the principles of diversity discussed in this chapter. These hormones require a rare element (iodine) for bioactivity they are synthesized as part of a very large precursor molecule (thyroglobuhn) they are stored in an intracellular reservoir (colloid) and there is peripheral conversion of T4 to T3, which is a much more active hormone. 

In addition to neutral loss scans, mass spectrometers can be used to detect other compounds in a different manner. Acylcamitines are fatty acid esters of carnitine. The masses of acylcamitines differ by the size of the fatty acid attached to it. The tandem mass spectrometer can detect these selectively as well because they all produce a similar product, in this case an ion rather than a molecule. Because it is an ion, it can be detected by the second mass separation device. The ion has a mass of 85 Da and is common to all acylcamitines. Performing a precursor ion scan of 85 Da (essentially a scan of only molecules that produce the 85 ion) reveals a selective analysis of acylcar-nitines, as shown in Fig. 14.2. Additional scans have been added to more selectively detect basic amino acids, free carnitine, short chain acylcamitines and a hormone, thyroxin (T4) which has amino acid components. 

Tyrosine (Tyr or Y) (4-hydroxyphenylalanine ((5)-2-amino-3-(4-hydroxyphenyl)-propanoic acid)) is a polar, neutral, aromatic amino acid with the formula H00CCH(NH2)CH2C6H50H and is the precursor of thyroxin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and the pigment melanin. Being the precursor amino acid for the thyroid gland hormone thyroxin, a defect in this may result in hypothyroidism. Tyr is extremely soluble in water, a property that has proven useful in isolating this amino acid from protein hydrolysates. The occurrence of tyrosine- 0-sulfate as a constituent of human urine and fibrinogen has been reported. ... 

Tyrosine is a precursor of thyroid hormones as well as L-dopa. Both thyroxine and L-dopa are employed in clinical medicine thyroxine to treat hypothyroid patients and L-dopa to treat patients with Parkinsonism. L-dopa is also the precursor to the pigment of the skin known as melanin. The enzyme that catalyzes the transformation of tyrosine into L-dopa, tyrosine hydroxylase, also catalyzes the transformation of L-dopa into melanin. Albinism is a genetic disease in which a mutation in the gene encoding tyrosine hydroxylase results in an inactive enzyme. People with albinism have no pigment in their skin, hair, or retina. 

The amino acids that are made available as a result of protein degradation in starvation are nsed as precursors of glucose, which is required for the brain. The decline in starvation-induced protein degradation is a result of the decreased requirement for glucose by the brain due to the increase in utilisation of ketone bodies. The qnestion arises, therefore, as to the mechanism by which the protein breakdown in muscle is reduced. Two answers, which are interdependent, have been put forward (i) decreased metabolic activity in tissues, and (ii) a decrease in the plasma level of thyroxine and hence triiodothyronine. 

Thyroid Hormones The thyroid hormones T4 (thyroxine) and T3 (triiodothyronine) are synthesized from the precursor protein thyroglobulin (Mr 660,000). Up to 20 Tyr residues in thyroglobulin are enzymatically iodinated... 

Thyroxine (T4) and the more potent triiodothyronine (T3) are cleaved from a large precursor protein called thyroglob-ulin. Thyroglobulin exists as a dimer of two identical polypeptides (Mr 330,000). It is a storage protein for iodine and can be considered a prohormone of the circulating thyroid hormones. Thyroglobulin is secreted into the lumen of the thyroid gland, where specific residues are iodinated in... 

Because thyroxine contains four iodine residues, this compound is also referred to by the abbreviation T4. Likewise, triiodothyronine contains three iodine residues, hence the abbreviation T3. There has been considerable discussion about which hormone exerts the primary physiologic effects. Plasma levels of T4 are much higher than T3 levels, but T3 may exert most of the physiologic effects on various tissues, which suggests that T4 is a precursor to T3 and that the conversion of T4 to T3 occurs in peripheral tissues.23 Regardless of which hormone ultimately affects cellular metabolism, both T4 and T3 are needed for normal thyroid function. 

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. 

L-thyroxine (T j or tetraiodo-L-thyronine) and liothyronine (Tg or triiodo-L-thyronine) are the natural hormones of the thyroid gland. is a less active precursor of Tj, which is the major mediator of physiological effect. In this chapter for therapeutic use is referred to as levothyroxine (the rINN, see p. 83) rather than levothyroxine (the former usage). 

Hyperthyroidism (excessive production of thyroid hormones) asually requires surgery, but before. surgery the patient mu.st be prepared by preliminary abolition of the hyper-thyroidi.sm through the use of antithyroid drugs. Thiourea and related eompounds. show an antithyroid activity, but they arc too toxic for clinical use. The more useful drugs are 2-thiouracil derivatives and a closely related 2-thioimidazolc derivative. All of these appear to have a similar mechanism of action (i.c.. prevention of the iodination of the precursors of thyroxine and triiodothyronine). The main difference in the compounds lies in their relative toxieities. 

The thyroid gland secretes two hormones, thyroxine (3,5,3, 5 -L tetraiodothyronine) and triiodothyronine (3,5>3 -L-triiodothyronine), which are commonly known as T4 and T3, respectively (Table 52-1). In addition, the thyroid gland secretes small amounts of biologically inactive 3,3, 5 -L-triiodothyronine (reverse T3 [rTa]) and minute quantities of monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are precursors of T3 and T4. The structures of these compounds are shown in Figure 52-1. 

A precursor to tyrosine and thyroid hormone (thyroxine), phenylalanine acts as an antidepressant, pain reliever, and appetite suppressant helps form collagen and supports memory, concentration, and thinking capabilities. 

Besides being fundamental constituents of proteins they are the parent substances from which powerful hormones are derived, for example, adrenaline (epinephrine), noradrenaline (norepinephrine), thyroxine and related substances, 5-hydroxytryptamine (enteramine, serotonin), and the plant hormone indoleacetic acid. Tryptophan is also the precursor of the B vitamin nicotinic acid and hence of part of the important pyridine nucleotides. All three aromatic amino acids are potential precursors of other substances having powerful physiological activity, for example, many of the alkaloids. Errors in the metabolism of the aromatic amino acids in man can give rise to sometimes serious, but fortunately comparatively rare, disorders such as alkaptonuria and phenylketonuria. The numerous metabolic pathways involved in aromatic amino acid metabolism therefore make an important as well as an interesting study. 

The answer is e. (Murray, pp 307-346. Scriver, pp 1667—1724. Sack, pp 121-138. Wilson, pp 287—3177) In humans, tyrosine can be formed by the hydroxylation of phenylalanine. This reaction is catalyzed by the enzyme phenylalanine hydroxylase. A deficiency of phenylalanine hydroxylase results in the disease called phenylketonuria [PKU(261600)]. In this disease it is usually the accumulation of phenylalanine and its metabolites rather than the lack of tyrosine that is the cause of the severe mental retardation ultimately seen. Once formed, tyrosine is the precursor of many important signal molecules. Catalyzed by tyrosine hydroxylase, tyrosine is hydroxylated to form L-dihydroxyphenylalanine (dopa), which in turn is decarboxylated to form dopamine in the presence of dopa decarboxylase. Then, norepinephrine and finally epinephrine are formed from dopamine. All of these are signal molecules to some degree. Dopa and inhibitors of dopa decarboxylase are used in the treatment of Parkinson s disease, a neurologic disorder. Norepinephrine is a transmitter at smooth-muscle junctions innervated by sympathetic nerve libers. Epinephrine and dopamine are catecholamine transmitters synthesized in sympathetic nerve terminals and in the adrenal gland. Tyrosine is also the precursor of thyroxine, the major thyroid hormone, and melanin, a skin pigment. 

Tyrosine is also the precursor of thyroxine, norepinephrine, epinephrine, DOPA, and the melanines. 

Iodine plays a key structural role in the thyroid hormones of humans and other mammals, primarily in the form of T3 (triiodothyronine) and T4 (thyroxine). In such samples precursor forms such as MIT (monoiodotyrosine) and DIT (diiodotyrosine) or isomer forms such as rT3 (reverse triiodothyronine) may also be measured. Iodine accounts for 65% of the molecular weight of T4 and 59% of the T3.15-20 mg of iodine is concentrated in the thyroid and hormones with 70% distributed in other tissues. In the cells of these tissues, iodide enters via the sodium-iodide symporter (NIS). 

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. 

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