New insights into the structure and mechanism of iodothyronine deiodinases

Abstract

Iodothyronine deiodinases are a family of enzymes that remove specific iodine atoms from one of the two aromatic rings in thyroid hormones (THs). They thereby fine-tune local TH concentrations and cellular TH 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 30 years. Hence, the structure generates new impetus for research 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 then discuss available compounds for modulating deiodinase activity for therapeutic purposes.

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

“…As the keto-enol tautomerism proposed for deiodination of the phenolic ring is not possible for the tyrosyl ring, ah alogen-bond-mediated cleavage of the C À Ib ond appears to be the most relevant mechanism for the deiodination of thyroid hormones by DIOs. [128] In agreement with this,modeling of the substrate complex of mDio3 cat places the Figure 9. A) X-ray crystal structure of mDio3 cat (PDB code:4TR4).…”

“…[193] Thei ntroduction of an aromatic ring onto PTU increased the inhibition of DIO1 at least tenfold. [128,194] When the concentration of DTT is low (0.2 mm), PTU can weakly inhibit DIO2. [194] In contrast to PTU,t he imidazole-based compounds MMI and MSeI were not effective inhibitors of DIO1.…”

Enzymatic Reductive Dehalogenation Controls the Biosynthesis of Marine Bacterial Pyrroles

“…For example, the peroxiredoxin-like mechanism favored for thyroid hormone aromatic deiodinase involves the formation of a selenyl iodide with a selenocysteine residue side chain selenolate that is proposed to resolve to a selenyl sulfide by an endogenous cysteine residue. (12) Formation of an active site cysteinyl bromide has also been proposed for the dehalogenation of the nonphysiological substrate 5-bromo-uridine by thymidylate synthase. (13) Lastly, formation of cob(II)alamin halide adduct was recently suggested from structure–function studies of two bacterial reductive dehalogenases.…”

The distribution and mechanism of iodotyrosine deiodinase defied expectations

“…However, more recent model studies suggest the potential for deiodination promoted by halogen and chalcogen bonding without loss of aromaticity [81, 82]. This later process is particularly appealing since it can be applied to dehalogenation of both the inner (phenoxy) and outer (phenol) rings of T4 (Scheme 1) [6]. An initial proposal of a polar mechanism for IYD based on Cys was also refuted after a mutant lacking all native Cys retained catalytic activity [26].…”

“…These processes are differentially promoted by three isoforms of iodothyronine deiodinase (ID) but all derive from the thioredoxin structural superfamily and all contain an active site selenocysteine [3]. Research interest in these enzymes has been intense [3, 4] and inspired most recently by publication of the first crystal structure of ID [5, 6]. …”