The thyroid gland of a healthy human adult with an adequate iodine intake produces predominantly the prohormone T4 and only a small amount of the bioactive hormone T3. It is generally accepted that, in humans, approximately 80% of circulating T3 is produced by enzymatic outer ring deiodination (ORD) of T4 in peripheral tissues. Alternatively, inner ring deiodination (IRD) of T4 produces the inactive metabolite reverse T3. Deiodination is also an important pathway by which T3 and reverse T3 are further metabolized. T3 largely undergoes IRD to the inactive compound T2, which is also the main metabolite produced from reverse T3 by ORD (Figure 1). Thus, the bioactivity of thyroid hormone is determined to an important extent by the enzyme activities responsible for the ORD (activation) or IRD (inactivation) of iodothyronines.

Fig1. Conversion of the prohormone T4 by outer ring deiodination (ORD) to the bioactive hormone T3 or by inner ring deiodination (IRD) to the metabolite reverse T3 , and further conversion of T3 by IRD and of reverse T3 by ORD to the common metabolite T2 .

Three iodothyronine deiodinases (D1– 3) are involved in the reductive deiodination of thyroid hormone (Figure 2). They are homologous proteins consisting of 249– 278 amino acids, with a single transmembrane domain located at the N- terminus. The deiodinases are inserted in cellular membranes such that the major part of the protein is exposed on the cytoplasmic surface. This is consistent with the reductive nature of the cytoplasmic compartment required for the deiodination process.

Fig2. Properties of the three iodothyronine deiodinases.

The most remarkable feature of all three deiodinases is the presence of a selenocysteine (Sec) residue in the centre of the amino acid sequence. As in other selenoproteins, this Sec residue is encoded by a UGA triplet, which in mRNAs for non- selenoproteins functions as a translation stop codon. The translation of the UGA codon into Sec requires the presence of a particular stem- loop structure in the 3′- untranslated region of the mRNA, termed Sec- insertion sequence (SECIS) element, Sec- tRNA, and several cellular proteins, including SECIS- binding protein (SBP2). A bona fide SECIS element has been identified in the mRNA of all deiodinases.

D1 is a membrane- bound enzyme expressed predominantly in liver, kidneys, and thyroid. It catalyses the ORD and/ or IRD of a variety of iodothyronine derivatives, although it is most effective in the ORD of reverse T3. In the presence of dithiothreitol (DTT) as the cofactor, D1 displays high Km and Vmax values. Hepatic D1 is probably a major site for the production of plasma T3 and clearance of plasma reverse T3. D1 activity in liver and kidney is increased in hyperthyroidism and decreased in hypothyroidism, representing the regulation of D1 activity by T3 at the transcriptional level.

The Sec residue is essential for the function of D1 since substitution with Cys reduces enzyme activity to 1%, while substitution with Leu yields a completely inactive protein. Rapid inactivation of D1 by iodoacetate is probably due to modification of the highly re active Sec residue. Thus, Sec is the catalytic centre of D1.

The different deiodinases require thiols as cofactor. Although reduced glutathione is the most abundant intracellular thiol, its activity is very low compared with the unnatural thiol DTT, which is often used in in vitro studies. Alternative endogenous cofactors include dihydrolipoamide, glutaredoxin, and thioredoxin. D1 shows ping- pong- type kinetics in catalysing the deiodination of iodothyronines by DTT. D1 activity is potently inhibited by propylthiouracil, and this inhibition is uncompetitive with substrate and competitive with cofactor. Together, these findings suggest that the catalytic mechanism of D1 involves the transfer of an iodonium ion (I+) from the substrate to the selenolate (Se−) group of the enzyme, generating a selenenyl iodide intermediate which is reduced back to native enzyme by thiols such as DTT or converted into a dead- end complex by propylthiouracil.

D2 is expressed primarily in brain, anterior pituitary, brown adipose tissue, thyroid, and to some extent also in skeletal muscle. In brain tissue, D2 mRNA has been localized in astrocytes, in particular also in tanycytes lining the third ventricle in the arcuate nucleus– median eminence region. D2 is a low- Km , low- capacity enzyme possessing only ORD activity, with a preference for T4 over reverse T3 as the substrate. The amount of T3 in brain, pituitary, and brown adipose tissue is derived to a large extent from local conversion of T4 by D2 and to a minor extent from plasma T3. The enzyme located in the anterior pituitary and the arcuate nucleus of the hypothalamus appears very important for the negative feedback regulation of TSH and TRH secretion.

In general, D2 activity is increased in hypothyroidism and de creased in hyperthyroidism. This is explained in part by substrate- induced inactivation of the enzyme by T4 and reverse T3 involving the ubiquitin- proteasome system [45]. However, inhibition of D2 activity and mRNA levels by T3 has also been demonstrated in the brain and pituitary. The substrate (T4, reverse T3) and product (T3)- dependent downregulation of D2 activity is important to maintain brain T3 levels in the face of changing plasma thyroid hormone levels.

In mammals, D2 mRNA contains a second UGA codon just upstream of a UAA stop codon. It remains to be determined to what extent this second TGA codon specifies the incorporation of a second Sec residue or acts as a translation stop codon. The amino acid sequence downstream of this second Sec is not required for enzyme activity.

D3 activity has been detected in different human tissues, brain, skin, liver, and intestine, where activities are much higher in the fetal stage than in the adult stage [45]. D3 is also abundantly ex pressed in placenta and pregnant uterus. D3 has only IRD activity, catalysing the inactivation of T4 and T3 with intermediate Km and Vmax values. D3 in tissues such as the brain is thought to play a role in the regulation of intracellular T3 levels, while its presence in placenta, pregnant uterus, and fetal tissues may serve to protect developing organs against undue exposure to active thyroid hormone. Indeed, fetal plasma contains low T3 (and high reverse T3) concentrations. However, local D2- mediated T3 production from T4 is crucial for brain development. Also in adult subjects, D3 appears to be an important site for clearance of plasma T3 and production of plasma reverse T3. In brain, but not in placenta, D3 activity is increased in hyperthyroidism and decreased in hypothyroidism, which at least in brain is associated with parallel changes in D3 mRNA levels.

In contrast to the marked decrease in hepatic and renal (but not thyroidal) D1 activities, there are only minor effects of selenium deficiency on tissue D2 and D3 activities. This may be explained by findings that the selenium state of different tissues varies greatly in selenium- deficient animals. In addition, the efficiency of the SECIS element to facilitate read- through of the UGA codon may differ among selenoproteins, which could result in the preferred in corporation of Sec into D2 or D3 over other selenoproteins.

The presence of Sec in a strongly conserved region of the proteins suggests the same catalytic mechanism for the different deiodinases. However, D2 and D3 are much less susceptible than D1 to the mechanism- based inhibitors propylthiouracil, iodoacetate, and gold thioglucose. This could be explained if the reactivity of the selenol group in D2 and D3 is much lower than that in D1. Indeed, substitution of Sec in D1 with the much less reactive Cys is associated with a dramatic decrease in its sensitivity to inhibition by gold thioglucose and propylthiouracil. Interestingly, the amino acid two positions downstream of the catalytic Sec residue (Ser in D1, Pro in D2 and D3) plays an important role in determining the reactivity of the catalytic Sec residue.

Mutations in SBP2 cause a multisystem disorder including abnormalities in deiodinase activity. Patients present growth and developmental delay, myopathy, infertility, and metabolic abnormalities. Some of these features are caused by increased accumulation of reactive oxygen species as a result from deficiencies of antioxidant selenoenzymes such as glutathione peroxidase. Thyroid function tests typically show normal TSH concentrations, elevated fT4 and rT3, accompanied by decreased T3 concentrations. The exact mechanisms underlying the abnormal thyroid parameters are not well understood, but the elevated T4 and rT3 levels over T3 levels indicate that ORD is predominantly affected.

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مواضيع ذات صلة

Role of Thyroid Hormone in Thermogenesis

Thyroid Hormone Transporters

Ghrelin, Leptin, and Energy Use

Coordination of Gastroenteropancreatic Hormone Release

Pancreatic, Biliary, and Intestinal Secretions

Hormone-Secreting Cells: Their Distribution in the Gastroenteropancreatic Complex

Leptin Functions as a Satiety Factor

Glucagon and Glucagon-like Peptides— Biosynthesis and Secretion

Adult Growth Hormone Deficiency

Hypopituitary crisis

Thyroid Replacement in TSH Deficiency

Glucagon’s Structure