Deiodinases are specialized enzymes that play a central role in managing thyroid hormones within the human body. As selenoproteins, deiodinases contain selenium, an element essential for their function. These enzymes activate or deactivate thyroid hormones by removing iodine atoms from their molecular structure. This regulation is fundamental for maintaining overall bodily function and metabolic balance.
Deiodinases: The Thyroid Hormone Regulators
The thyroid gland primarily secretes thyroxine (T4), a prohormone with minimal biological activity. For the body to effectively use thyroid hormones, T4 must convert into its active form, triiodothyronine (T3), or be converted into inactive forms like reverse T3 (rT3). This conversion process is controlled by deiodinase enzymes.
Deiodinases remove iodine atoms from T4, transforming it into T3. T3 is the biologically active hormone that binds to receptors inside cells, influencing gene expression and regulating various physiological processes. Without deiodinases, the body cannot fully utilize thyroid hormones, impacting metabolism, growth, and development.
The regulation of thyroid hormones by deiodinases is a dynamic process. These enzymes ensure that the right amount of active thyroid hormone is available in specific tissues at the appropriate time. This localized control is crucial for maintaining metabolic equilibrium.
The Specific Roles of Different Deiodinase Types
Three main types of deiodinases, D1, D2, and D3, each have distinct functions and tissue distributions, contributing to the regulation of thyroid hormones. These enzymes are characterized by their ability to remove iodine atoms from either the outer or inner ring of the thyroid hormone molecule, leading to activation or inactivation.
Deiodinase 1 (D1)
Deiodinase 1 (D1) is primarily found in the liver, kidneys, and thyroid gland, and also in the central nervous system, though its expression in the human brain is low. D1 can both activate T4 to T3 by removing an iodine from the outer ring and inactivate T4 to rT3 or T3 to T2 by removing an iodine from the inner ring. Its role is significant in producing circulating T3, especially during hyperthyroidism.
Deiodinase 2 (D2)
Deiodinase 2 (D2) is predominantly expressed in the brain, pituitary gland, brown adipose tissue, and skeletal muscle. D2 primarily converts T4 into active T3 by removing an iodine atom from the outer ring, increasing local T3 concentrations. D2 is located in the endoplasmic reticulum membrane, positioning it close to the cell nucleus where T3 exerts its effects. This enzyme maintains stable T3 levels in specific tissues, even if circulating T4 levels fluctuate.
Deiodinase 3 (D3)
Deiodinase 3 (D3) primarily inactivates thyroid hormones by removing an iodine atom from the inner ring of T4 to produce rT3, or from T3 to produce T2. Both rT3 and T2 are biologically inactive. D3 is found in the central nervous system and skin in adulthood, but its expression is highest during embryonic development and in the placenta, where it protects developing tissues from excessive thyroid hormone exposure. D1 and D3 are located in the plasma membrane, with D3’s catalytic domain largely protruding towards the extracellular space.
How Deiodinase Imbalance Affects Health
Imbalanced deiodinase activity can lead to various health issues. Both insufficient and excessive deiodinase activity can disrupt thyroid hormone signaling, impacting metabolic processes and overall well-being.
Impaired T4 to T3 conversion, often due to reduced D1 or D2 activity, can contribute to hypothyroidism, a condition characterized by an underactive thyroid. Conversely, excessive conversion of T4 to T3, from increased D1 or D2 activity, can lead to hyperthyroidism, an overactive thyroid state. Genetic variations in deiodinase genes, such as those affecting D2, can also influence localized T3 availability and contribute to tissue-specific hypothyroidism.
Deiodinases also play a role in Non-Thyroidal Illness Syndrome (NTIS), also known as “sick euthyroid syndrome,” occurring during severe illness or starvation. In NTIS, deiodinase activity shifts to conserve energy; D1 and D2 activity decreases, reducing T4 to T3 conversion, while D3 activity increases, accelerating the inactivation of T3 and T4. This adaptive response results in lower circulating T3 levels, a common abnormality in NTIS patients.
Proper deiodinase function is important for normal development, especially in infants. Thyroid hormones are important for neurological development. Impaired deiodinase activity during fetal development, particularly involving D3, can lead to neurological impairment. High D3 activity in certain tumors can lead to “consumptive hypothyroidism” by rapidly destroying circulating thyroid hormone.