L-thyroxine(T4)

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Pubchem(5819)
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'''Thyroxine''', or 3,5,3',5'-tetra­iodothyronine (often abbreviated as '''T<sub>4</sub>'''), a form of [[thyroid hormones]] is the major [[hormone]] secreted by the [[follicular cells]] of the [[thyroid]] gland.
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The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (MONOIODOTYROSINE) and the coupling of iodotyrosines (DIIODOTYROSINE) in the THYROGLOBULIN. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form TRIIODOTHYRONINE which exerts a broad spectrum of stimulatory effects on cell metabolism.
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Lipinski’s “Rule of Five” Prediction for a Compound’s ABSORPTION OR PERMEABILITY PROPERTIES.
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'''Synthesis'''
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The hormone was synthesised in 1927 by British chemists [[Charles Robert Harington]] and [[George Barger]].
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Thyroxine is synthesized via the iodination of tyrosines (MONOIODOTYROSINE) and the coupling of iodotyrosines (DIIODOTYROSINE) in the THYROGLOBULIN. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form TRIIODOTHYRONINE which exerts a broad spectrum of stimulatory effects on cell metabolism.
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T<sub>4</sub> is transported in blood, with 99.95% of the secreted T<sub>4</sub> being protein bound, principally to [[thyroxine-binding globulin]] (TBG), and, to a lesser extent, to [[transthyretin]] and [[serum albumin]]. T<sub>4</sub> is involved in controlling the rate of metabolic processes in the body and influencing physical development.  Administration of thyroxine has been shown to significantly increase the concentration of [[nerve growth factor]] in the brains of adult mice.<ref>Walker et al. (27 April 1979) Thyroxine increases nerve growth factor concentration in adult mouse brain. ''Science.'' Vol. 204, No. 4391. pp. 427 - 429.</ref>
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Note: Thyroxine is a [[prohormone]] and a reservoir for the active thyroid hormone [[triiodothyronine]] (T<sub>3</sub>). T<sub>4</sub> is converted in the tissues by [[deiodinase]]s to T<sub>3</sub>. The "D" isomer is called "[[Dextrothyroxine]]"<ref>{{MeshName|Dextrothyroxine}}</ref> and is used as a lipid modifying agent.<ref>{{ATC|C10|AX01}}</ref> The half-life of thyroxine once released into the blood circulatory system is about 1 week.
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==Reactions==
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:[[image:Iodothyronine_deiodinase.png|thumb|400px|left|Transformations]]{{clear}}
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==References==
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<references/>
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'''Pubchem'''(5819)
{| border="1;width:100%; height:200px;style=text-align:center"
{| border="1;width:100%; height:200px;style=text-align:center"
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|+'''Table I:'''
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|+'''Lipinski’s “Rule of Five” for Thyroxine'''
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! style="background:brown; color:white" |4
! style="background:brown; color:white" |4
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! style="background:brown; color:white" |0
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|GOOD
|GOOD
|INDETERMINATE
|INDETERMINATE
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|}
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KEGG Pathway(C01829)
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'''KEGG Pathway'''(C01829)
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Tyrosine metabolism
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*Tyrosine metabolism
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Neuroactive ligand-receptor interaction
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*Neuroactive ligand-receptor interaction
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Autoimmune thyroid disease
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*Autoimmune thyroid disease
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Comment Thyroid hormone
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synthesized on thyroglobulin  
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'''Comment''' Thyroid hormone synthesized on thyroglobulin  
{| border="1;width:100%; height:200px;style=text-align:center"
{| border="1;width:100%; height:200px;style=text-align:center"
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|+'''Table I:'''
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|+'''List of PDB file having T4 as Ligand'''
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! style="background:brown; color:white" |MMDB ID
! style="background:brown; color:white" |MMDB ID
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|1ICT
|1ICT
|Wojtczak A, Luft JR, Cody VStructural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complexJ. Biol. Chem. v268, p.6202-6206
|Wojtczak A, Luft JR, Cody VStructural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complexJ. Biol. Chem. v268, p.6202-6206
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The crystal structure of human transthyretin (TTR) complexed with milrinone (2-methyl-5-cyano-3,4"-bipyridin-6(1H)-one), a positive inotropic cardiac agent, has been refined to R = 17.4% for 8-1.9-A resolution data. This report provides the first detailed description of protein interactions for an inotropic bipyridine agent which is an effective thyroid hormone binding competitor to transthyretin....
 
|-
|-
|19209
|19209
|1IE4
|1IE4
|Wojtczak ACrystal structure of rat transthyretin at 2.5 A resolution: first report on a unique tetrameric structureActa Biochim. Pol. v44, p.505-517
|Wojtczak ACrystal structure of rat transthyretin at 2.5 A resolution: first report on a unique tetrameric structureActa Biochim. Pol. v44, p.505-517
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The first observation of a unique tetrameric molecular structure of transthyretin from rat (rTTR, prealbumin) is reported. The structure has been determined by X-ray diffraction using molecular replacement and the structure of human transthyretin (hTTR) as a starting model. Crystals of native rat transthyretin are tetragonal, space group P4(3)2(1)2, and have four independent monomers in the asymmetric unit of the crystal lattice....
 
|-
|-
|22897
|22897
|1HK1
|1HK1
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|
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|Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
|-
|-
|22898
|22898
|1HK2
|1HK2
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|
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|Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
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|-
|22893
|22893
|1HK3
|1HK3
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|
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|Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
|-
|-
|22900
|22900
|1HK4
|1HK4
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|Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
|-
|-
|22901
|22901
|1HK5
|1HK5
|Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
|Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
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Human serum albumin (HSA) is the major protein component of blood plasma and serves as a transporter for thyroxine and other hydrophobic compounds such as fatty acids and bilirubin. We report here a structural characterization of HSA-thyroxine interactions. Using crystallographic analyses we have identified four binding sites for thyroxine on HSA distributed in subdomains IIA, IIIA, and IIIB....
 
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|-
|28581
|28581
|1SN0
|1SN0
|Eneqvist T, Lundberg E, Karlsson A, Huang S, Santos CR, Power DM, Sauer-Eriksson AEHigh resolution crystal structures of piscine transthyretin reveal different binding modes for triiodothyronine and thyroxineJ. Biol. Chem. v279, p.26411-26416
|Eneqvist T, Lundberg E, Karlsson A, Huang S, Santos CR, Power DM, Sauer-Eriksson AEHigh resolution crystal structures of piscine transthyretin reveal different binding modes for triiodothyronine and thyroxineJ. Biol. Chem. v279, p.26411-26416
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Transthyretin (TTR) is an extracellular transport protein involved in the distribution of thyroid hormones and vitamin A. So far, TTR has only been found in vertebrates, of which piscine TTR displays the lowest sequence identity with human TTR (47%). Human and piscine TTR bind both thyroid hormones 3,5,3"-triiodo-l-thyronine (T(3)) and 3,5,3",5"-tetraiodo-l-thyronine (thyroxine, T(4))....
 
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|-
|3173
|3173
|1Y0X
|1Y0X
|Sandler B, Webb P, Apriletti JW, Huber BR, Togashi M, Cunha Lima ST, Juric S, Nilsson S, Wagner R, Fletterick RJ, Baxter JDThyroxine-thyroid hormone receptor interactionsJ. Biol. Chem. v279, p.55801-55808
|Sandler B, Webb P, Apriletti JW, Huber BR, Togashi M, Cunha Lima ST, Juric S, Nilsson S, Wagner R, Fletterick RJ, Baxter JDThyroxine-thyroid hormone receptor interactionsJ. Biol. Chem. v279, p.55801-55808
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Thyroid hormone (TH) actions are mediated by nuclear receptors (TRs alpha and beta) that bind triiodothyronine (T(3), 3,5,3"-triiodo-l-thyronine) with high affinity, and its precursor thyroxine (T(4), 3,5,3",5"-tetraiodo-l-thyronine) with lower affinity. T(4) contains a bulky 5" iodine group absent from T(3). Because T(3) is buried in the core of the ligand binding domain (LBD), we have predicted that TH analogues with 5" substituents should fit poorly into the ligand binding pocket and perhaps behave as antagonists....
 
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|5764
|5764
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|2ROX
|2ROX
|Wojtczak A, Luft JR, Cody VStructural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complexJ. Biol. Chem. v268, p.6202-6206
|Wojtczak A, Luft JR, Cody VStructural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complexJ. Biol. Chem. v268, p.6202-6206
-
The crystal structure of human transthyretin (TTR) complexed with milrinone (2-methyl-5-cyano-3,4"-bipyridin-6(1H)-one), a positive inotropic cardiac agent, has been refined to R = 17.4% for 8-1.9-A resolution data. This report provides the first detailed description of protein interactions for an inotropic bipyridine agent which is an effective thyroid hormone binding competitor to transthyretin....
 
|-
|-
|67282
|67282
Line 94: Line 105:
|1ETA
|1ETA
|Hamilton JA, Steinrauf LK, Braden BC, Liepnieks J, Benson MD, Holmgren G, Sandgren O, Steen LThe x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolutionJ. Biol. Chem. v268, p.2416-2424
|Hamilton JA, Steinrauf LK, Braden BC, Liepnieks J, Benson MD, Holmgren G, Sandgren O, Steen LThe x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolutionJ. Biol. Chem. v268, p.2416-2424
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The x-ray crystal structures of normal human transthyretin (prealbumin) and the amyloidogenic Val-30-Met variant have been refined at 1.7-A resolution to R-values of 0.168 and 0.179, respectively, for 19,882 and 20,362 reflections (Fobs > 2.0 sigma). Standard deviations for stereochemical parameters are 0.018 and 0.022 A for bond distances, 0.030 and 0.038 A for angle distances, and 0.035 and 0.070 A for planar 1-4 distances....
 
|-
|-
|899
|899
|1ETB
|1ETB
|Hamilton JA, Steinrauf LK, Braden BC, Liepnieks J, Benson MD, Holmgren G, Sandgren O, Steen LThe x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolutionJ. Biol. Chem. v268, p.2416-2424
|Hamilton JA, Steinrauf LK, Braden BC, Liepnieks J, Benson MD, Holmgren G, Sandgren O, Steen LThe x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolutionJ. Biol. Chem. v268, p.2416-2424
-
The x-ray crystal structures of normal human transthyretin (prealbumin) and the amyloidogenic Val-30-Met variant have been refined at 1.7-A resolution to R-values of 0.168 and 0.179, respectively, for 19,882 and 20,362 reflections (Fobs > 2.0 sigma). Standard deviations for stereochemical parameters are 0.018 and 0.022 A for bond distances, 0.030 and 0.038 A for angle distances, and 0.035 and 0.070 A for planar 1-4 distances....
 
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|}
|}
{| border="1;width:100%; height:200px;style=text-align:center"
{| border="1;width:100%; height:200px;style=text-align:center"
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|+'''Table I:'''
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|+'''Physiochemical Properties'''
|-
|-
! style="background:brown; color:white" |Physical Property
! style="background:brown; color:white" |Physical Property
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{| border="1;width:100%; height:200px;style=text-align:center"
{| border="1;width:100%; height:200px;style=text-align:center"
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|+'''Table I:'''
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|+'''Toxicity'''
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! style="background:brown; color:white" |Organism  
! style="background:brown; color:white" |Organism  

Current revision

Thyroxine, or 3,5,3',5'-tetra­iodothyronine (often abbreviated as T4), a form of thyroid hormones is the major hormone secreted by the follicular cells of the thyroid gland.

Synthesis

The hormone was synthesised in 1927 by British chemists Charles Robert Harington and George Barger.

Thyroxine is synthesized via the iodination of tyrosines (MONOIODOTYROSINE) and the coupling of iodotyrosines (DIIODOTYROSINE) in the THYROGLOBULIN. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form TRIIODOTHYRONINE which exerts a broad spectrum of stimulatory effects on cell metabolism.

T4 is transported in blood, with 99.95% of the secreted T4 being protein bound, principally to thyroxine-binding globulin (TBG), and, to a lesser extent, to transthyretin and serum albumin. T4 is involved in controlling the rate of metabolic processes in the body and influencing physical development. Administration of thyroxine has been shown to significantly increase the concentration of nerve growth factor in the brains of adult mice.<ref>Walker et al. (27 April 1979) Thyroxine increases nerve growth factor concentration in adult mouse brain. Science. Vol. 204, No. 4391. pp. 427 - 429.</ref>

Note: Thyroxine is a prohormone and a reservoir for the active thyroid hormone triiodothyronine (T3). T4 is converted in the tissues by deiodinases to T3. The "D" isomer is called "Dextrothyroxine"<ref>Template:MeshName</ref> and is used as a lipid modifying agent.<ref>Template:ATC</ref> The half-life of thyroxine once released into the blood circulatory system is about 1 week.


[edit] Reactions

Image:Iodothyronine deiodinase.png
Transformations
Template:Clear

[edit] References

<references/>


Pubchem(5819)

Lipinski’s “Rule of Five” for Thyroxine
4 3 2 1 0
GOOD INDETERMINATE INDETERMINATE INDETERMINATE POOR

KEGG Pathway(C01829)

  • Tyrosine metabolism
  • Neuroactive ligand-receptor interaction
  • Autoimmune thyroid disease

Comment Thyroid hormone synthesized on thyroglobulin

List of PDB file having T4 as Ligand
MMDB ID PDB ID Reference
18746 1ICT Wojtczak A, Luft JR, Cody VStructural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complexJ. Biol. Chem. v268, p.6202-6206
19209 1IE4 Wojtczak ACrystal structure of rat transthyretin at 2.5 A resolution: first report on a unique tetrameric structureActa Biochim. Pol. v44, p.505-517
22897 1HK1 Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
22898 1HK2 Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
22893 1HK3 Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
22900 1HK4 Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
22901 1HK5 Petitpas I, Petersen CE, Ha CE, Bhattacharya AA, Zunszain PA, Ghuman J, Bhagavan NV, Curry SStructural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemiaProc. Natl. Acad. Sci. U. S. A. v100, p.6440-6445
28581 1SN0 Eneqvist T, Lundberg E, Karlsson A, Huang S, Santos CR, Power DM, Sauer-Eriksson AEHigh resolution crystal structures of piscine transthyretin reveal different binding modes for triiodothyronine and thyroxineJ. Biol. Chem. v279, p.26411-26416
3173 1Y0X Sandler B, Webb P, Apriletti JW, Huber BR, Togashi M, Cunha Lima ST, Juric S, Nilsson S, Wagner R, Fletterick RJ, Baxter JDThyroxine-thyroid hormone receptor interactionsJ. Biol. Chem. v279, p.55801-55808
5764 2CEO Zhou A, Wei Z, Read RJ, Carrell RWStructural mechanism for the carriage and release of thyroxine in the bloodProc. Natl. Acad. Sci. U. S. A. v103, p.13321-13326

The hormones that most directly control tissue activities in health and disease are delivered by two noninhibitory members of the serpin family of protease inhibitors, thyroxine-binding globulin (TBG) and corticosteroid-binding globulin. The structure of TBG bound to tetra-iodo thyroxine, solved here at 2.8 A, shows how the thyroxine is carried in a surface pocket on the molecule....

5764 2ROX Wojtczak A, Luft JR, Cody VStructural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complexJ. Biol. Chem. v268, p.6202-6206
67282 2RIW Description The Reactive Loop Cleaved Human Thyroxine Binding Globulin Complexed With Thyroxine.

Deposition: Zhou A, Wei Z, Stanley PLD, Read RJ, Stein PE, Carrell RW, 2007/10/12

898 1ETA Hamilton JA, Steinrauf LK, Braden BC, Liepnieks J, Benson MD, Holmgren G, Sandgren O, Steen LThe x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolutionJ. Biol. Chem. v268, p.2416-2424
899 1ETB Hamilton JA, Steinrauf LK, Braden BC, Liepnieks J, Benson MD, Holmgren G, Sandgren O, Steen LThe x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolutionJ. Biol. Chem. v268, p.2416-2424
Physiochemical Properties
Physical Property Value Units Temp (deg C) Source
Melting Point 235.5 deg C EXP
log P (octanol-water) 4.120 (none) EST
Water Solubility 1.05E-04 mg/L 25 EST
Vapor Pressure 1.24E-17 mm Hg 25 EST
Henry's Law Constant 7.91E-19 atm-m3/mole 25 EST
Atmospheric OH Rate Constant 4.17E-11 cm3/molecule-sec 25 EST
Toxicity
Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
child TDLo oral 328ug/kg (0.328mg/kg) CARDIAC: PULSE RATE INCREASE WITHOUT FALL IN BP,VASCULAR: BP LOWERING NOT CHARACTERIZED IN AUTONOMIC SECTION Pediatrics. Vol. 73, Pg. 313, 1984.Link to PubMed
man TDLo oral 63ug/kg (0.063mg/kg) PTIONS",CARDIAC: PULSE RATE INCREASE WITHOUT FALL IN BP Journal of Toxicology, Clinical Toxicology. Vol. 20, Pg. 517, 1983.,Link to PubMed
man TDLo oral 10286ug/kg (10.286mg/kg) BEHAVIORAL: EXCITEMENT,CARDIAC: PULSE RATE INCREASE WITHOUT FALL IN BP,

GASTROINTESTINAL: NAUSEA OR VOMITING

Veterinary and Human Toxicology. Vol. 41, Pg. 323, 1999.Link to PubMed
women TDLo oral 400ug/kg/2D-I (0.4mg/kg) BEHAVIORAL: COMA,CARDIAC: ARRHYTHMIAS (INCLUDING CHANGES IN CONDUCTION) Intensive Care Medicine. Vol. 13, Pg. 33, 1987.Link to PubMed
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