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, tri- and 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.

Figure 1

Thyroid hormones and the side products diiodotyrosine (DIT) and monoiodotyrosine (MIT) formed during their biosynthesis.

Figure 2

Iodide uptake, transport, metabolism, and salvage in thyroid follicular cells.

Figure 3

The proposed involvement of selenocysteine (Sec) in the mechanism of iodothyronine deiodinase.

Figure 4

N-Alkylpyridones mimic the non-aromatic tautomer of a proposed intermediate formed during catalytic dehalogenation by iodotyrosine deiodinase.

Figure 5

The crystal structure of iodotyrosine deiodinase. (A) Identical subunits of the dimeric enzyme are differentiated by color to illustrate their general fold and assembly. Disordered regions connect the internal sequences marked by the five- and six-pointed stars. (B) The electrostatic surface of the enzyme is illustrated with an overlay of the structure induced within the co-crystal of IYD·MIT.

Figure 5

The crystal structure of iodotyrosine deiodinase. (A) Identical subunits of the dimeric enzyme are differentiated by color to illustrate their general fold and assembly. Disordered regions connect the internal sequences marked by the five- and six-pointed stars. (B) The electrostatic surface of the enzyme is illustrated with an overlay of the structure induced within the co-crystal of IYD·MIT.

Figure 6

Numerous polar contacts are established between the substrate MIT, FMN and the active site residues of IYD.

Figure 7

The locations of mutations in Human IYD are mapped onto the corresponding residues within the structure of murine IYD.