Tyrosine is a non-essential amino acid that is the direct precursor of the thyroid hormones T3 (triiodothyronine) and T4 (thyroxine) — the hormones that regulate basal metabolic rate, thermogenesis, heart rate, and cardiac output, and that are essential for normal development, growth, and cognitive function. Tyrosine is taken up by the thyroid follicular cells from the blood and is the substrate for the enzyme thyroid peroxidase (TPO), which catalyses the iodination of the tyrosine residues on thyroglobulin (the precursor protein of T3 and T4) and the coupling of the iodinated tyrosine residues to form T3 and T4. The thyroid hormones that are synthesised from tyrosine are then stored in the colloid of the thyroid follicle as part of the thyroglobulin molecule and are released into the blood upon stimulation by thyroid-stimulating hormone (TSH) from the anterior pituitary. The tyrosine-based synthesis of thyroid hormones is one of the most important metabolic pathways in human physiology, and its dysfunction produces the characteristic clinical syndrome of hypothyroidism — fatigue, weight gain, cold intolerance, bradycardia, constipation, depression, and the slowing of virtually every organ system in the body.
Thyroid Hormone Synthesis and the Sodium Iodide Symporter
The thyroid follicular cell is the functional unit of the thyroid gland — it takes up iodide from the blood via the sodium iodide symporter (NIS), oxidises the iodide to iodine via the thyroid peroxidase enzyme, iodinates the tyrosine residues on thyroglobulin, and couples the iodinated tyrosine residues to form T3 and T4. The NIS is expressed on the basolateral membrane of the thyroid follicular cell and uses the sodium gradient that is generated by the Na+/K+-ATPase to drive the active transport of iodide into the cell against a concentration gradient. The activity of the NIS is regulated by TSH — when TSH is elevated (as in hypothyroidism, when the negative feedback from T3 and T4 on the pituitary is reduced), the NIS is upregulated, the uptake of iodide by the thyroid is increased, and the synthesis of thyroid hormones is increased. The NIS is the target of the pharmacological action of perchlorate and of other NIS inhibitors, which block the uptake of iodide by the thyroid and which are used in the treatment of hyperthyroidism and of thyroid cancer.
The importance of tyrosine for thyroid hormone synthesis is underscored by the observation that tyrosine deficiency (which is rare in isolation but can develop in people with inadequate protein intake or with specific genetic defects in tyrosine metabolism) produces a reduction in thyroid hormone synthesis that is independent of the iodide status. Even when iodide is abundant, if tyrosine is not available in adequate amounts, the thyroid cannot synthesise sufficient T3 and T4 to maintain normal metabolic rate. This tyrosine-dependent component of thyroid hormone synthesis is one of the mechanisms by which chronic protein malnutrition (which reduces tyrosine availability) contributes to the development of hypothyroidism and to the metabolic slowing that characterises the malnutrition state.
T3 and T4 and Basal Metabolic Rate
The thyroid hormones T3 and T4 regulate basal metabolic rate (BMR) through multiple mechanisms — they increase the expression of the uncoupling proteins (UCPs) in mitochondria, particularly UCP1 in brown adipose tissue, which uncouple oxidative phosphorylation and generate heat instead of ATP; they increase the Na+/K+-ATPase activity in virtually every cell in the body, which increases the resting energy expenditure; they increase the heart rate and cardiac output by increasing the sensitivity of the heart to catecholamines; and they increase the expression of the genes that regulate lipolysis and fatty acid oxidation in adipose tissue, which increases the rate of fat oxidation and reduces fat storage. The net effect of these T3/T4 actions is a marked increase in BMR and in total daily energy expenditure — the thyroid hormones are in this sense the master regulators of the metabolic rate, and their deficiency produces the metabolic slowing that is one of the most characteristic features of hypothyroidism.
Practical Application
For general tyrosine supplementation (as a thyroid support strategy), the evidence-based approach is to ensure adequate tyrosine intake from dietary protein (tyrosine is abundant in meat, fish, poultry, eggs, dairy, and soybeans) and to supplement with tyrosine at 500-1,000mg daily when thyroid function is suboptimal or when symptoms of hypothyroidism are present. Tyrosine should be taken in the morning (on an empty stomach) because it competes with the other large neutral amino acids for the same intestinal transporters, and the presence of protein in the gut reduces its absorption. Tyrosine is also the precursor of L-DOPA, dopamine, adrenaline, and noradrenaline, and supplementation with tyrosine has been studied for its effects on mood, cognitive function, and stress response. For comprehensive thyroid support, tyrosine pairs well with iodine (which is the raw material for thyroid hormone synthesis — the RDA is 150mcg daily for adults, and most people obtain adequate iodine from iodised salt and from seafood), with selenium (which is required for the deiodinase enzymes that convert T4 to T3 and which protects the thyroid from oxidative damage), with zinc (which is required for the synthesis of TSH and for the function of the thyroid hormone receptor), and with iron (which is required for the activity of thyroid peroxidase and which is often deficient in people with hypothyroidism).
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