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Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism.

ABSTRACT: Local levels of active thyroid hormone (3,3',5-triiodothyronine) are controlled by the action of activating and inactivating iodothyronine deiodinase enzymes. Deiodinases are selenocysteine-dependent membrane proteins catalyzing the reductive elimination of iodide from iodothyronines through a poorly understood mechanism. We solved the crystal structure of the catalytic domain of mouse deiodinase 3 (Dio3), which reveals a close structural similarity to atypical 2-Cys peroxiredoxin(s) (Prx). The structure suggests a route for proton transfer to the substrate during deiodination and a Prx-related mechanism for subsequent recycling of the transiently oxidized enzyme. The proposed mechanism is supported by biochemical experiments and is consistent with the effects of mutations of conserved amino acids on Dio3 activity. Thioredoxin and glutaredoxin reduce the oxidized Dio3 at physiological concentrations, and dimerization appears to activate the enzyme by displacing an autoinhibitory loop from the iodothyronine binding site. Deiodinases apparently evolved from the ubiquitous Prx scaffold, and their structure and catalytic mechanism reconcile a plethora of partly conflicting data reported for these enzymes.

SUBMITTER: Schweizer U

PROVIDER: S-EPMC4115520 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism.

Schweizer Ulrich U Schlicker Christine C Braun Doreen D Köhrle Josef J Steegborn Clemens C

Proceedings of the National Academy of Sciences of the United States of America 20140707 29

Local levels of active thyroid hormone (3,3',5-triiodothyronine) are controlled by the action of activating and inactivating iodothyronine deiodinase enzymes. Deiodinases are selenocysteine-dependent membrane proteins catalyzing the reductive elimination of iodide from iodothyronines through a poorly understood mechanism. We solved the crystal structure of the catalytic domain of mouse deiodinase 3 (Dio3), which reveals a close structural similarity to atypical 2-Cys peroxiredoxin(s) (Prx). The ...[more]

PMID: 25002520

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Project description:PurposeThe development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non-small-cell lung cancer (NSCLC) who had a functional thyroid.Materials and methodsThyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases.ResultsUpon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels.ConclusionAn off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.

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Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism.

Publications

Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism.

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