Biosynthesis of 3-Iodothyronamine From T4 in Murine Intestinal Tissue.
The endogenous metabolite 3-iodothyronamine (3-T1AM) induces strong hypothermia and bradycardia at pharmacological doses. Although its biosynthesis from thyroid hormone precursors appears likely, the sequence and sites of reactions are still controversial: studies in T4-substituted thyroid cancer patients lacking functional thyroid tissue suggested extrathyroidal 3-T1AM production, whereas studies using labeled T4 in mice indicated intrathyroidal formation. However, because the patients received T4 orally, whereas the mice were injected ip, we hypothesized that 3-T1AM synthesis requires the intestinal passage of T4. Using the everted gut sac model in combination with mass spectrometry, we demonstrate 3-T1AM production from T4 in mouse intestine via several deiodination and decarboxylation steps. Gene expression analysis confirmed the expression of all 3 deiodinases as well as ornithine decarboxylase (ODC) in intestine. Subsequent experiments employing purified human ODC revealed that this enzyme can in fact mediate decarboxylation of 3,5-T2 and T4 to the respective thyronamines (TAMs), demonstrating that the intestine expresses the entire molecular machinery required for 3-T1AM biosynthesis. Interestingly, TAM production was strongly affected by the antithyroid treatment methimazole and perchlorate independently of thyroid status, limiting the validity of the respective mouse models in this context. Taken together, our data demonstrate intestinal 3-T1AM biosynthesis from T4 involving decarboxylation through ODC with subsequent deiodination, and explain the apparent discrepancy between 3-T1AM serum levels in patients substituted orally and mice injected ip with T4. Identifying ODC as the first enzyme capable of decarboxylating thyroid hormone, our findings open the path to further investigations of TAM metabolism on molecular and cellular levels.
Institut für Experimentelle Endokrinologie (C.S.H., E.R., I.L., U.S., J.K.), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Karolinska Institutet (C.S.H., T.W., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden; Ziel Research Center of Nutrition and Food Science (T.W., H.D.), Abteilung Biochemie, Technische Universität München, 85354 Freising, Germany; Institut für Biochemie und Molekularbiologie (U.S.), Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany; and Center of Brain, Behavior and Metabolism (J.M.), Medizinische Klinik 1, Universität zu Lübeck, 23562 Lübeck, Germany.
Carolin S
CS
Hoefig
Institut für Experimentelle Endokrinologie (C.S.H., E.R., I.L., U.S., J.K.), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Karolinska Institutet (C.S.H., T.W., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden; Ziel Research Center of Nutrition and Food Science (T.W., H.D.), Abteilung Biochemie, Technische Universität München, 85354 Freising, Germany; Institut für Biochemie und Molekularbiologie (U.S.), Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany; and Center of Brain, Behavior and Metabolism (J.M.), Medizinische Klinik 1, Universität zu Lübeck, 23562 Lübeck, Germany.
Tilo
T
Wuensch
Institut für Experimentelle Endokrinologie (C.S.H., E.R., I.L., U.S., J.K.), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Karolinska Institutet (C.S.H., T.W., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden; Ziel Research Center of Nutrition and Food Science (T.W., H.D.), Abteilung Biochemie, Technische Universität München, 85354 Freising, Germany; Institut für Biochemie und Molekularbiologie (U.S.), Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany; and Center of Brain, Behavior and Metabolism (J.M.), Medizinische Klinik 1, Universität zu Lübeck, 23562 Lübeck, Germany.
Eddy
E
Rijntjes
Institut für Experimentelle Endokrinologie (C.S.H., E.R., I.L., U.S., J.K.), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Karolinska Institutet (C.S.H., T.W., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden; Ziel Research Center of Nutrition and Food Science (T.W., H.D.), Abteilung Biochemie, Technische Universität München, 85354 Freising, Germany; Institut für Biochemie und Molekularbiologie (U.S.), Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany; and Center of Brain, Behavior and Metabolism (J.M.), Medizinische Klinik 1, Universität zu Lübeck, 23562 Lübeck, Germany.
Ina
I
Lehmphul
Institut für Experimentelle Endokrinologie (C.S.H., E.R., I.L., U.S., J.K.), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Karolinska Institutet (C.S.H., T.W., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden; Ziel Research Center of Nutrition and Food Science (T.W., H.D.), Abteilung Biochemie, Technische Universität München, 85354 Freising, Germany; Institut für Biochemie und Molekularbiologie (U.S.), Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany; and Center of Brain, Behavior and Metabolism (J.M.), Medizinische Klinik 1, Universität zu Lübeck, 23562 Lübeck, Germany.
Hannelore
H
Daniel
Institut für Experimentelle Endokrinologie (C.S.H., E.R., I.L., U.S., J.K.), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Karolinska Institutet (C.S.H., T.W., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden; Ziel Research Center of Nutrition and Food Science (T.W., H.D.), Abteilung Biochemie, Technische Universität München, 85354 Freising, Germany; Institut für Biochemie und Molekularbiologie (U.S.), Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany; and Center of Brain, Behavior and Metabolism (J.M.), Medizinische Klinik 1, Universität zu Lübeck, 23562 Lübeck, Germany.
Ulrich
U
Schweizer
Institut für Experimentelle Endokrinologie (C.S.H., E.R., I.L., U.S., J.K.), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Karolinska Institutet (C.S.H., T.W., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden; Ziel Research Center of Nutrition and Food Science (T.W., H.D.), Abteilung Biochemie, Technische Universität München, 85354 Freising, Germany; Institut für Biochemie und Molekularbiologie (U.S.), Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany; and Center of Brain, Behavior and Metabolism (J.M.), Medizinische Klinik 1, Universität zu Lübeck, 23562 Lübeck, Germany.
Jens
J
Mittag
Institut für Experimentelle Endokrinologie (C.S.H., E.R., I.L., U.S., J.K.), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Karolinska Institutet (C.S.H., T.W., J.M.), Department of Cell and Molecular Biology, 17177 Stockholm, Sweden; Ziel Research Center of Nutrition and Food Science (T.W., H.D.), Abteilung Biochemie, Technische Universität München, 85354 Freising, Germany; Institut für Biochemie und Molekularbiologie (U.S.), Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany; and Center of Brain, Behavior and Metabolism (J.M.), Medizinische Klinik 1, Universität zu Lübeck, 23562 Lübeck, Germany.
Josef
J
Köhrle
D000818:Animals; D007413:Intestinal Mucosa / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000378:metabolism; D051379:Mice; D013970:Thyronines / Q000096:biosynthesis*; D013974:Thyroxine / Q000378:metabolism* / Q000494:pharmacology; D000097564:Iodothyronine Deiodinase Type II
D007453:Iodide Peroxidase; D013970:Thyronines; D013974:Thyroxine; D000097564:Iodothyronine Deiodinase Type II; C487948:3-iodothyronamine; C109812:iodothyronine deiodinase type I