TH are derived from the iodinated amino acid tyrosine and coupled to their typical diphenylether structure. Metabolic modifications of TH lead to activation, inactivation or novel quality not exerted by the parent molecule L-T4. Phenolic-5′-(outer) and tyrosyl-3′-(inner ring) deiodination are well known metabolic pathways. Activating 5′deiodination of T4 to T3 is catalysed by two distinct DIO1 and DIO2 selenoproteins, with distinct biological characteristics, developmental profiles, tissue distribution and regulation. DIO2 significantly contributes to local T3 production while DIO1, highly expressed in hepatic, renal and thyroid tissue, mainly generates T3 for systemic circulation. DIO3 represents the key enzyme for T4 and T3 inactivation in various tissues, diseases and during development. Inappropriate function of DIO3 during development alters the HPT set point and over-expression in juvenile hemangioma leads to consumptive hypothyroidism.
TH metabolism at the alanine side chain generates Tetrac and Triac, both found in the blood. Tetrac antagonizes T4 and T3 activation of the cell membrane αvβ3 integrin receptor, possibly involved in tumour proliferation and angiogenesis. Triac, a potent TR ligand, is clinically used in TH resistance without producing concomitant T3-typic cardiac effects. Recently, 3T1AM has been re-discovered as a potent cooling thyroid TH metabolite. Aromatic amino acid decarboxylase had been proposed as the enzyme catalysing decarboxylation of the TH alanin side chain to thyronamines, but this hypothesis has recently been refuted. Oxidative diphenylether-ring cleavage inactivates TH generating DIT, found in septic serum and probably generated by activated macrophages and leucocytes. Conjugation of the 4′ phenolic OH group with sulphate or glucuronide inactivates TH and leads to their biliary excretion and enterohepatic recycling.
Several major and minor pathways of TH metabolism have been characterized during the last decades, but still detection of novel, relevant TH metabolites such as 3T1AM brings surprises for thyroid community. Supported by DFG and BMBF grants.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.
05 - 09 May 2012
European Society of Endocrinology