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Thyronamines Are Isozyme-Specific Substrates of Deiodinases

Institut für Experimentelle Endokrinologie und Endokrinologisches Forschungszentrum der Charité EnForCé (S.P., J.K.), Charité–Universitätsmedizin Berlin, Campus Virchowklinikum, D-13353 Berlin, Germany; Federal Institute for Risk Assessment (T.H., G.B.), D-12277 Berlin, Germany; Department of Physiology and Pharmacology (T.S.S.), Oregon Health and Science University, Portland, Oregon 97239; Department of Chemistry and Biochemistry–Organic Chemistry (R.S., B.K.), Free University of Berlin, D-14195 Berlin, Germany

Address all correspondence and requests for reprints to: Prof. Dr. Josef Köhrle, Institut für Experimentelle Endokrinologie und Endokrinologisches Forschungszentrum der Charité EnForCé, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: josef.koehrle{at}charite.de.

3-Iodothyronamine (3-T₁AM) and thyronamine (T₀AM) are novel endogenous signaling molecules that exhibit great structural similarity to thyroid hormones but apparently antagonize classical thyroid hormone (T₃) actions. Their proposed biosynthesis from thyroid hormones would require decarboxylation and more or less extensive deiodination. Deiodinases (Dio1, Dio2, and Dio3) catalyze the removal of iodine from their substrates. Because a role of deiodinases in thyronamine biosynthesis requires their ability to accept thyronamines as substrates, we investigated whether thyronamines are converted by deiodinases. Thyronamines were incubated with isozyme-specific deiodinase preparations. Deiodination products were analyzed using a newly established method applying liquid chromatography and tandem mass spectrometry (LC-MS/MS). Phenolic ring deiodinations of 3,3',5'-triiodothyronamine (rT₃AM), 3',5'-diiodothyronamine (3',5'-T₂AM), and 3,3'-diiodothyronamine (3,3'-T₂AM) as well as tyrosyl ring deiodinations of 3,5,3'-triiodothyronamine (T₃AM) and 3,5-diiodothyronamine (3,5-T₂AM) were observed with Dio1. These reactions were completely inhibited by the Dio1-specific inhibitor 6n-propyl-2-thiouracil (PTU). Dio2 containing preparations also deiodinated rT₃AM and 3',5'-T₂AM at the phenolic rings but in a PTU-insensitive fashion. All thyronamines with tyrosyl ring iodine atoms were 5(3)-deiodinated by Dio3-containing preparations. In functional competition assays, the newly identified thyronamine substrates inhibited an established iodothyronine deiodination reaction. By contrast, thyronamines that had been excluded as deiodinase substrates in LC-MS/MS experiments failed to show any effect in the competition assays, thus verifying the former results. These data support a role for deiodinases in thyronamine biosynthesis and contribute to confining the biosynthetic pathways for 3-T₁AM and T₀AM.

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