Outer ring deiodination

Triiodothyronine (3, 5,3-L-triiodothyronine, T3) is a thyroid hormone. It is producedby outer ring deiodination of thyroxine (T4) in peripheral tissues. The biologic activity of T3 is 3-8 times higher than that of T4. T3 is 99.7% protein-bound and is effective in its free non-protein-bound form. The half-life of triiodothyronine is about 19 h. The daily tur nover of T3 is 75%. Triiodothyronine acts via nuclear receptor binding with subsequent induction of protein synthesis. Effects of thyroid hormones are apparent in almost all organ systems. They include effects on the basal metabolic rate and the metabolisms of proteins, lipids and carbohydrates. 

Abbreviations BAT, brown adipose tissue BrAc, /V-bromoacetyl- BSA, bovine serum albumin CNS, central nervous system DEP, diethylpyrocarbonatc DIT, diiodotyrosine DTT, dithiothreitol G, glu-curonide Grx, glutaredoxin GSH, reduced glutathione GSSG, oxidized glutathione IRD. inner ring deiodination MIT, monoiodotyrosine ORD, outer ring deiodination PTU, propylthiouracil S, sulfate rT3, 3,3, 5 -triiodothyronine (reverse T,) Trx, thioredoxin T2, diiodothyronine T3, 3,3, 5-triiodothyronine T4, 3,3, 5,5 -tetraiodothyronine (thyroxine). 

Fig. 3. The main pathways for TH monodeiodination. ORD, outer-ring deiodination IRD, inner-ring deiodination.

Deiodination In order to initiate TH action, T4 originating from the thyroid gland a must be activated in tissues by outer ring deiodination (ORD) to form T3. To balance the activation pathway, both T4 and T3 are irreversibly inactivated by monodeiodination of the tyrosyl ring of the iodothyronines, called inner ring deiodination (IRD). Mammals and birds have three types of deiodinases type I deiodinase (Dl) with ORD and IRD activity, type II (D2) with only ORD activity, and type 111 with only IRD activity VisserT. J. (1990). 

Three types of deiodinases are currently known, and these are distinguished from each other primarily based on their location, substrate preference, and susceptibility to inhibitors. Type I deiodinase is found in liver and kidney and catalyzes both inner ring and outer ring deiodination (i.e., T4 to T3 and rTs to 3,3 -T2). Type II deiodinase catalyzes mainly outer ring deiodination (i.e., T4 to T3 and T3 to 3,3 -T2) and is found in brain and the pituitary. Type III deiodinase is the principal source of rTs and is present in brain, skin, and placenta (14). 

As discussed earlier, T4 is considered to be a prohormone, and its peripheral metabolism occurs in two ways outer ring deiodination by the enzyme 5 -D, which yields T3, and inner ring deiodination by the enzyme 5-D, which yields rT3, for which there is no known biological function (Fig. 34.4). In humans, deiodination is the most important metabolic pathway of the hormone, not only because of its dual role in... 

Outer ring deiodination by the enzyme 5 -D, which yields T3. 

Having defined critical conditions for the examination of outer ring deiodination, similar techniques were applied to the Type III or inner ring deiodinase activity (17-19). The results were anticipated by the initial studies of the enzyme homogenates. The Type III enzyme prefers T3 as a substrate, follows sequential, rather than ping-pong, kinetics and is insensitive to PTU at 10 M (Table 1). Despite the fact that T3 is the preferred substrate for the Type III activity, it is this enzyme which produces rT3 from T4 in the central nervous system. 

T3 (rT3), that is metabolically inert. Thus outerring deiodination is the step-up process to increase metabolic activity and the inner-ring deiodination is the step-down inactivation process. Further deiodination of the molecule abolishes hormonal activity. Drugs such as ipodate, beta-blockers, and corticosteroids influence 5 -deiodinase, resulting in low T3 and high rT3 levels in serum. 

The most important pathway for the metabolism of T4 is monodeiodination. The removal of an iodide from the outer ring of T4 yields T3. Since the affinity of nuclear TRs is much higher for T3 than T4, outer ring monodeiodination of T4 to yield T3 produces a more active metabolite. Conversely, removal of an iodide from the inner ring of T4 yields an inactive metabolite, rTj. Both T3 and rT3 may undergo subsequent deiodinations to yield totally deiodinated thyronine (To). 

Type I iodothyronine deiodinase is defined as the enzyme which catalyses the (mono)deiodination of the inner or the outer ring of different iodothyronines and which is inhibited by jrM concentrations of PTU [5-8]. In rats and humans, such enzyme activities are present at high levels in liver, kidneys and interestingly also in thyroid, and at low levels in many other tissues [5-8]. The deiodinase is associated with the microsomal fractions of these tissues but is only active in the presence of a cytoplasmic cofactor [5-8], Also, in the absence of cytosol, deiodinase activity is stimulated by simple thiols such as dithiothreitol (DTT) but the physiological cofactor has not yet been identified with certainty. The effects of synthetic and natural thiols will be discussed in Section 2.5. 

As discussed in previous sections, the stepwise deiodination of T4 is mediated by at least three different enzymes. Deiodination of the outer ring of T4 and reverse T3 is mediated by the type I and II enzymes while deiodination of the inner ring of T4 and T3 is catalysed by the type I and III enzymes. The contribution of the different enzymes to the peripheral production and clearance of T3 and rT3 can be estimated using PTU as a specific inhibitor of the type I deiodinase (for potential pitfalls of this approach, see Section 3.3). Thyroid hormone has a positive effect on the type I and type III enzymes but down-regulates the type II deiodinase. 

Reaction catalyzed 5-deiodination (outer ring) 5-deiodination (outer ring) 5-deiodination (inner ring)... 

DEIODINATION SITE OUTER AND INNER RING OUTER RING INNER RING... 

The reaction of thyronine derivative 56b under the same conditions yielded the deiodinated product 57b (65% from 56b) and selenenyl iodide 55 (55% from 49). These results provide the chanical evidence for the proposed deiodination of a 2,6-diiodophenol derivative by a selenol. It is notable that, in the reaction of 56b, only deiodination at the outer ring took place—similar to the conversion of T4 to T3 in the ID-1 catalytic cycle. 

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