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Iodothyronine deiodinases, a ubiquitous family of selenoenzymes, are key tissue-specific regulators of intracellular thyroid hormone availability and signaling. This chapter reviews current information supporting the notion that the altered expression and/or activity of deiodinases contribute to the pathophysiology of diverse clinical disorders. Experimental and clinical evidence establishes an association of polymorphisms in deiodinase genes with mood, affective and cognitive functioning, as well as type 2 diabetes mellitus and lipid metabolism. Similarly, an imbalance in the activating and inactivating deiodinase pathways may promote cell proliferation and/or invasiveness of different types of neoplasms. Although a clear-cut picture has not yet been achieved, emerging data support the notion that the deiodinase-dependent thyroid hormone transcriptional footprint has a profound functional impact in health and disease.

We review the role of iodothyronine deiodinases (IDs) in the evolution of vertebrate thyroidal systems within the larger context of biological metabolism of halogens. Since the beginning of life, the ubiquity of organohalogens in the biosphere has provided a major selective pressure for the evolution and conservation of cellular mechanisms specialized in halogen metabolism. Among naturally available halogens, iodine emerged as a critical component of unique developmental and metabolic messengers. Metabolism of iodinated compounds occurs in the three major domains of life, and invertebrate deuterostomes possess several biochemical traits and molecular homologs of vertebrate thyroidal systems, including ancestral homologs of IDs identified in urochordates. The finely tuned cellular regulation of iodometabolite uptake and disposal is a remarkable event in evolution and might have been decisive for the explosive diversification of ontogenetic strategies in vertebrates.