New insights into the structure and mechanism of iodothyronine deiodinases

Titelangaben

Schweizer, Ulrich ; Steegborn, Clemens:
New insights into the structure and mechanism of iodothyronine deiodinases.
In: Journal of Molecular Endocrinology. Bd. 55 (2015) Heft 3 . - R37-R52.
ISSN 1479-6813
DOI: https://doi.org/10.1530/JME-15-0156

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Abstract

Iodothyronine deiodinases are a family of enzymes that remove specific iodine atoms from one of the two aromatic rings in thyroid hormones. They thereby fine-tune local thyroid hormone concentrations and cellular thyroid hormone signaling. Deiodinases catalyze a remarkable biochemical reaction, i. e. the reductive elimination of a halogenide from an aromatic ring. In metazoans, deiodinases depend on the rare amino acid selenocysteine. The recent solution of the first experimental structure of a deiodinase catalytic domain allowed for a reappraisal of the many mechanistic and mutagenesis data that had been accumulated over more than thirty years. Hence, the structure generates new impetus for efforts directed at understanding catalytic mechanism, substrate specificity, and regulation of deiodinases. This review will focus on structural and mechanistic aspects of iodothyronine deiodinases and briefly compare these enzymes with dehalogenases, which catalyze related reactions. A general mechanism for the selenium-dependent deiodinase reaction will be described, which integrates the mouse deiodinase 3 crystal structure and biochemical studies. We will summarize further, sometimes isoform-specific molecular features of deiodinase catalysis and regulation, and we will shortly discuss available compounds for modulating deiodinase activity for therapeutic purposes.