3-Iodothyronamine: A High Potency Metabolic Hormone and its Potential for Therapeutic Applications

Abstract

Open Access Review Articlegreater potency and receptor affinity than other thyronamines [1]. Production and regulationDue to their structural similarities, it was initially hypothesized that T1AM was derived from thyroxine (T4), accomplished through a series of one decarboxylation and three deiodination enzymatic reactions [9]. This conversion of T4 or Triiodothyronine (T3) into T1AM has not been directly demonstrated (Figure 1). It is still an attractive hypothesis for a number of reasons. Decarboxylation and deiodination are known to play an important role in thyroid hormone catabolism [10]. Thyronamines are also able to serve as substrates for deiodinases [11]. This reaction series could explain a functional role of reverse Triiodothyronine (rT3) as an intermediate product of T1AM synthesis, as rT3 is the inactive deiodination product of T4 with no known physiological function, yet it is produced in equal ratios to the active compound T3 [12]. The essential decarboxylation reaction however has not been biologically characterized, as synthesis of thyronamines from T4 or T3 would require decarboxylation to occur prior to deamination, as the amine group is retained in thyronamines. This reaction order is not usually thought to occur in thyroid hormone catabolism, but the enzyme that catalyzes this reaction, named aromatic amino acid decarboxylase, is widely expressed and possesses a broad range of substrate specificity. Though this series of reactions seems highly plausible, a more recent study using heavy isotope tracing of exogenous T4 in a mouse model of induced hypothyroidism did not demonstrate any conversion of T4 to T1AM [13]. As a result of induced hypothyroidism, T1AM levels were greatly diminished as well, but exogenous T4 administration was not able to replenish serum T1AM levels despite successfully restoring circulating T4 and T3 concentrations. This suggests that production of T1AM uses the same biosynthetic factors required for the synthesis of T4 and provides with the possibility that, T1AM is synthesized de novo in a divergent manner from that of T4. Abstract3-Iodothyronamide (T1AM) is a naturally produced endogenous hormone like molecule. Only recently it has been discovered in the past decade, the proceeding body of research emerging from its initial discovery has revealed a substantial capacity of T1AM as a new potential hormone that affects numerous physiological processes and organs. Initially, it was hypothesized to be a byproduct of Thyroid Hormone (TH) metabolism; however, the current body of evidence suggests that its production and physiological function appear to be uncoupled and dramatically divergent from that of TH. This review summarizes the physiological and biochemical effects of T1AM reported in the literature along with its proposed mechanisms of action and production pathways. The physiological effects of T1AM appear to be dose specific, in some cases exerting opposing effects in the same biological processes. Uptake, storage, and degree of effect appear to be tissue specific...

Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut—From Gut to Brain?

“…Application of an endogenous biogenic cryogen derived from a hormone provides a rather safe and valuable “lead compound” to be tested and developed by the pharmaceutical industry for various medical applications …” (16). “ From the current body of literature, potential therapeutic applications with T1AM are quite apparent, ranging from sleep/torpidity induction, conferring protection against ischemic injury, and anti-obesogenic by inducing increased metabolic reliance on lipid oxidation ” (17). “ The major endogenous thyroid hormone metabolite 3-iodothyronamine (3-T1AM) exerts marked cryogenic, metabolic, cardiac and central nervous system actions.…”

“…Neuronal membrane as well as vesicular transporters for dopamine and noradrenaline (45, 53) and all subtypes of muscarinic acetylcholine receptors (54) are functionally blocked in the micromolar or sub-micromolar range. Other identified “targets” are cited in review articles (16, 17, 55). One very high-affinity binding site, apolipoprotein B-100 (ApoB-100), is mentioned here for two reasons.…”