TY - JOUR
T1 - Thyronamines are isozyme-specific substrates of deiodinases
AU - Piehl, S.
AU - Heberer, T.
AU - Balizs, G.
AU - Scanlan, T. S.
AU - Smits, R.
AU - Koksch, B.
AU - Köhrle, Josef
PY - 2008/6
Y1 - 2008/6
N2 - 3-Iodothyronamine (3-T1AM)andthyronamine (T0AM)are novel endogenous signaling molecules that exhibit great structural similarity to thyroid hormones but apparently antagonize classical thyroid hormone (T 3) 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′-T 2AM 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.
AB - 3-Iodothyronamine (3-T1AM)andthyronamine (T0AM)are novel endogenous signaling molecules that exhibit great structural similarity to thyroid hormones but apparently antagonize classical thyroid hormone (T 3) 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′-T 2AM 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.
UR - http://www.scopus.com/inward/record.url?scp=44249088058&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44249088058&partnerID=8YFLogxK
U2 - 10.1210/en.2007-1678
DO - 10.1210/en.2007-1678
M3 - Article
C2 - 18339710
AN - SCOPUS:44249088058
SN - 0013-7227
VL - 149
SP - 3037
EP - 3045
JO - Endocrinology
JF - Endocrinology
IS - 6
ER -