Efficient use and recycling of the micronutrient iodide in mammals

Abstract

Daily ingestion of iodide alone is not adequate to sustain production of the thyroid hormones, triand tetraiodothyronine. Proper maintenance of iodide in vivo also requires its active transport into the thyroid and its salvage from mono-and diiodotyrosine that are formed in excess during hormone biosynthesis. The enzyme iodotyrosine deiodinase responsible for this salvage is unusual in its ability to catalyze a reductive dehalogenation reaction dependent on a flavin cofactor, FMN. Initial characterization of this enzyme was limited by its membrane association, difficult purification and poor stability. The deiodinase became amenable to detailed analysis only after identification and heterologous expression of its gene. Site-directed mutagenesis recently demonstrated that cysteine residues are not necessary for enzymatic activity in contrast to precedence set by other reductive dehalogenases. Truncation of the N-terminal membrane anchor of the deiodinase has provided a soluble and stable source of enzyme sufficient for crystallographic studies. The structure of an enzyme•substrate co-crystal has become invaluable for understanding the origins of substrate selectivity and the mutations causing thyroid disease in humans.

A Switch between One- and Two-electron Chemistry of the Human Flavoprotein Iodotyrosine Deiodinase Is Controlled by Substrate

“…There is little mechanistic logic for IYD to preferentially bind an electron-rich form of its substrate and then introduce an additional two electrons into this species. Still, the 2Ј-hydroxyl group of FMN could function in a manner complementary to that described for acyl-CoA dehydrogenase and BluB if the non-aromatic keto form of the I-Tyr was generated in the active site as an electrophilic acceptor of reducing equivalents (2). The only evidence currently supporting such an intermediate derives from the high affinity of IYD for non-aromatic pyridone analogs designed to mimic the keto form of the halotyrosines (44).…”

“…Efficient use of dietary iodide depends on its accumulation in the thyroid as managed by a sodium-iodide symporter (1). Iodide is also salvaged from iodinated tyrosine by-products as promoted by iodotyrosine deiodinase (IYD) 3 (2). Nature's reliance on iodine for signaling is highly unusual, and thyroid hormones represent the only example of this in higher organisms.…”

New insights into the structure and mechanism of iodothyronine deiodinases

“…It is a membrane-associated enzyme and its crystal structure was solved after establishing efficient recombinant expression (Thomas et al 2009). The NADPHdependence of IYD was lost upon solubilization, however, a finding that has been explained by loss of an unidentified intermediate electron carrier connecting NADPH and IYD (Rokita et al 2010). The exact mechanism of IYD is not established, but it is clear that it does not involve a catalytic thiol and relies instead on the presence of a protein-bound FMN (Hu et al 2015; Fig.…”

Inhibition of intrathyroidal dehalogenation by iodide

“…In addition, a physiological role for ID1 as a scavenger enzyme has been recently proposed due to its capacity to remove iodide from reverse triiodothyronine (rT 3 ) and other inactive and sulfated iodothyronines (St Germain et al 2009). tDh and the three iodothyronine selenodeiodinases are the only enzymes known to catalyze reductive dehalogenation in mammals, though they are structurally and mechanistically different (Rokita et al 2010). However, and in spite of the importance of dehalogenation, little is known about the regulation of this intrathyroidal enzymatic system.…”