THE IMPORTANCE OF THE 3' AND 5'-IODO GROUPS
 

Liothyronine (T3) and levothyroxine (T4) are identical in structure with the exception that T4 has a 5'-iodo group (I[19] in 3-D structure on left) while T3 does not.  Both T4 and T3 are active as thyroid hormones; however, T3 is three to five times as active as T4.  Obviously, the extra atom is detracting from activity, but why? When T4 is written as a conventional two-dimensional structure (as above), the 3' and 5' iodine atoms appear to be identical (note that the ring has a plane of symmetry).  However from the discussions above, it is known that the active conformation is one in which the aromatic rings are perpendicular and thus positions 3' and 5' are not equivalent.  The 3' position, I[17] in the 3-D model, is distal (i.e., farthest away) to the L-alanine side chain, while the 5' position, I[19] in the 3-D model, is proximal to the side chain. While it should be obvious from viewing the 3-D molecule that the 3' and 5' positions are different, this fact can be verified by measuring the distance between the carboxylic acid and the 3' and 5' iodo groups.  Click on either of the oxygen atoms of the carboxylic acid, O[23] or O[24], and make sure a white ring appears around the selected atom.  Move your mouse cursor over the 3' and 5' iodo atoms (don't click the iodo atoms here) and note the distances between the oxygens and the iodo atoms.  You should observe a significant difference in the distances which hopefully will reinforce the concepts of proximal and distal.

As stated above, liothyronine (T3, R= H) is 3 to 5 times as active as thyroxine (T4, R = I).  The extra iodine atom present in T4 causes steric hindrance in binding to the thyroid receptor.  This steric hindrance is responsible for the lower activity of T4 and is illustrated in the models shown below.

The Binding of T4
Shown below is T4 binding to the thyroid receptor.  Notice that the 3'-iodo group is bound to a large hydrophobic cavity (represented by the black line surrounding the structure).  Further note that a similar hydrophobic cavity for the 5'-iodo group does not exist.  Hence, steric hindrance will decrease the binding of T4 to the thyroid receptor.

The Binding of T3
Shown below is T3 binding to the thyroid receptor.  Like T4, the 3'-Iodo group binds to the large hydrophobic cavity.  Unlike T4, however, the lack of a 5'-Iodo group allows T3 to perfectly fit into the receptor.  The steric hindrance present in T4 is not seen with T3; therefore, T3 is more active (i.e., more potent) than T4.

Question 4
Using the information and explanations given throughout this exercise, how would you expect the activity of compound A to compare with the activity of T3 and T4?  To answer this question, all you need to do is rank order these three compounds.

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