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== Human TTR ==
== Human TTR ==


=== Fonctions ===
=== Functions ===




Identified on 1942, Human transthyretin (TTR) ([[1dvq]]) is a transport protein encoded by the TTR gene, located on chromosome 18 <ref> Wallace MR, Naylor SL, Kluve-Beckerman B, Long GL, McDonald L, Shows TB, Benson MD, Localization of the human prealbumin gene to chromosome 18 [archive], Biochem Biophys Res Commun, 1985;129:753–758</ref>. It is mainly present in the plasma and synthetized by the liver, but also in the cerebrospinal fluid produced by the choroid plexus of the brain, and in retinal pigment epithelium. This protein was originally called prealbumin as it runs faster than albumin ([[1bm0]]) during SDS-PAGE <ref> Seibert FB, Nelson JW. Electrophoretic study of the blood protein response in tuberculosis. J Biol Chem 1942; 143: 29–38. </ref>. After discovering its binding and transport ability to thyroxine (T4), it was given the name of “thyroxine-binding prealbumin” (TBPA). Indeed, its role is crucial as it allows essential thyroid hormones, implied in cell differenciation, growth and metabolic regulation<ref> Wikipedia contributors. "Thyroid hormones." Wikipedia, The Free Encyclopedia. Wikipedia, The Free Encyclopedia, 10 Jan. 2020. Web. 16 Jan. 2020.</ref>, to pass through the bloodstream. Finally, its actual name refers to an additional carrier function: '''trans'''ports '''thyr'''oxine and '''retin'''ol (one form of vitamin A). Recently, it has been found that TTR also has a role in proteolysis, and in the nervous system, implicated axonal growth, neurogenesis, and nerve regeneration<ref name= "Vieira">Vieira M, Saraiva MJ, Transthyretin: a multifaceted protein [archive], Biomol Concepts, 2014;5:45–54</ref>.
Identified on 1942, Human transthyretin (TTR) ([[1dvq]]) is a transport protein encoded by the TTR gene, located on chromosome 18 <ref> Wallace MR, Naylor SL, Kluve-Beckerman B, Long GL, McDonald L, Shows TB, Benson MD, Localization of the human prealbumin gene to chromosome 18, Biochem Biophys Res Commun, 1985;129:753–758 doi:https://doi.org/10.1016/0006-291X(85)91956-4 </ref>. It is mainly present in the plasma and synthetized by the liver, but also in the cerebrospinal fluid produced by the choroid plexus of the brain, and in retinal pigment epithelium. This protein was originally called prealbumin as it runs faster than albumin ([[1bm0]]) during SDS-PAGE <ref> Seibert FB, Nelson JW. Electrophoretic study of the blood protein response in tuberculosis. J Biol Chem 1942; 143: 29–38. </ref>. After discovering its binding and transport ability to thyroxine (T4), it was given the name of “thyroxine-binding prealbumin” (TBPA). Indeed, its role is crucial as it allows essential thyroid hormones, implied in cell differenciation, growth and metabolic regulation<ref> Wikipedia contributors. "Thyroid hormones." Wikipedia, The Free Encyclopedia. [https://en.wikipedia.org/wiki/Thyroid_hormones] (accessed on Jan. 16 2020)</ref>, to pass through the bloodstream. Finally, its actual name refers to an additional carrier function: '''trans'''ports '''thyr'''oxine and '''retin'''ol (one form of vitamin A). Recently, it has been found that TTR also has a role in proteolysis, and in the nervous system, implicated axonal growth, neurogenesis, and nerve regeneration<ref name= "Vieira">Vieira M, Saraiva MJ, Transthyretin: a multifaceted protein, Biomol Concepts, 2014;5:45–54 doi: https://doi.org/10.1515/bmc-2013-0038</ref>.




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The channel has three sets of small hydrophobic depressions, termed '''halogen binding pockets (HBPs)'''. But then, when the side chain of the TTR changes of conformation, these pockets can realise more hydrogen bonds with other molecules, they can be donor or acceptor.  Thus, they had this name due to their ability to bind the iodines of thyroxine (T4) its natural ligand <ref name="Labaudinière">Labaudinière R. Chapter 9 Discovery and Development of Tafamidis for the Treatment of TTR Familial Amyloid Polyneuropathy. Orphan Drugs and Rare Diseases. Aug 2014 202-229. DOI:https://doi.org/10.1039/9781782624202-00202</ref>.
The channel has three sets of small hydrophobic depressions, termed '''halogen binding pockets (HBPs)'''. But then, when the side chain of the TTR changes of conformation, these pockets can realise more hydrogen bonds with other molecules, they can be donor or acceptor.  Thus, they had this name due to their ability to bind the iodines of thyroxine (T4) its natural ligand <ref name="Labaudinière">Labaudinière R. Chapter 9 Discovery and Development of Tafamidis for the Treatment of TTR Familial Amyloid Polyneuropathy. Orphan Drugs and Rare Diseases. Aug 2014 202-229. doi:https://doi.org/10.1039/9781782624202-00202</ref>.
At the entry of the binding site, the TTR has a hydrophilic tail, into which the four iodine atoms of the ligand are placed. The dimer interface of the TTR is divided in two part, the inner and the outer binding cavity. The outermost pockets <scene name='82/829358/Hbp1/3'>HBP1</scene> and <scene name='82/829358/Hbp1prim/3'>HBP1'</scene> are located between the side chains of <scene name='82/829358/Hbp1aa/1'>Ala 108, Thr 106, Met 13 and Lys 15</scene> <ref name= "Klabunde">PMID: 10742177</ref>. The central <scene name='82/829358/Hbp2/2'>HBP2</scene> and <scene name='82/829358/Hbp2prime/1'>HBP2'</scene> are formed by the side chains of <scene name='82/829358/Hbp2aa/1'>Leu 110, Ala 109, Lys 15, and Leu 17</scene>, it is primarily hydrophobic with polar or electrostatic contributions from the carbonyl groups of Lys 15, Ala 108 and Ala 109. The innermost binding pockets, <scene name='82/829358/Hbp3/3'>HBP3</scene> and <scene name='82/829358/Hbp3prim/2'>HBP3'</scene>, are located between the side chains of <scene name='82/829358/Hbp3aa/2'>Ser 117, Thr 119, Ala 108 and Leu 110</scene>. Their surfaces are composed of aliphatic methyl and methylene groups, as well as the Ser 117 hydroxyl group, the carbonyl groups of Ser 117, Thr 118 and Ala 108, and the main chain NH groups of Thr 119, Ala 109 and Leu 110.  
At the entry of the binding site, the TTR has a hydrophilic tail, into which the four iodine atoms of the ligand are placed. The dimer interface of the TTR is divided in two part, the inner and the outer binding cavity. The outermost pockets <scene name='82/829358/Hbp1/3'>HBP1</scene> and <scene name='82/829358/Hbp1prim/3'>HBP1'</scene> are located between the side chains of <scene name='82/829358/Hbp1aa/1'>Ala 108, Thr 106, Met 13 and Lys 15</scene> <ref name= "Klabunde">PMID: 10742177</ref>. The central <scene name='82/829358/Hbp2/2'>HBP2</scene> and <scene name='82/829358/Hbp2prime/1'>HBP2'</scene> are formed by the side chains of <scene name='82/829358/Hbp2aa/1'>Leu 110, Ala 109, Lys 15, and Leu 17</scene>, it is primarily hydrophobic with polar or electrostatic contributions from the carbonyl groups of Lys 15, Ala 108 and Ala 109. The innermost binding pockets, <scene name='82/829358/Hbp3/3'>HBP3</scene> and <scene name='82/829358/Hbp3prim/2'>HBP3'</scene>, are located between the side chains of <scene name='82/829358/Hbp3aa/2'>Ser 117, Thr 119, Ala 108 and Leu 110</scene>. Their surfaces are composed of aliphatic methyl and methylene groups, as well as the Ser 117 hydroxyl group, the carbonyl groups of Ser 117, Thr 118 and Ala 108, and the main chain NH groups of Thr 119, Ala 109 and Leu 110.  


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Thyroxine (T4) is the main precursor of T3 hormone (triiodothyronine). They both control physiological processes like urinary water absorption and also cell metabolism. T4 is  produced by the thyroid gland. Its concentration is used to diagnose thyroid diseases <ref name= "t4">Eshar, D., Nau, M. R., & Pohlman, L. M. (2017). PLASMA THYROXINE (T4) CONCENTRATION IN ZOO-KEPT BLACK-TAILED PRAIRIE DOGS (CYNOMYS LUDOVICIANUS). Journal of Zoo and Wildlife Medicine, 48(1), 116–120. doi:10.1638/2016-0073.1 </ref>.
Thyroxine (T4) is the main precursor of T3 hormone (triiodothyronine). They both control physiological processes like urinary water absorption and also cell metabolism. T4 is  produced by the thyroid gland. Its concentration determination is used to diagnose thyroid diseases <ref name= "t4">Eshar, D., Nau, M. R., & Pohlman, L. M. (2017). PLASMA THYROXINE (T4) CONCENTRATION IN ZOO-KEPT BLACK-TAILED PRAIRIE DOGS (CYNOMYS LUDOVICIANUS). Journal of Zoo and Wildlife Medicine, 48(1), 116–120. doi: http://dx.doi.org/10.1638/2016-0073.1 </ref>.
Two hormone binding sites are located at the dimer–dimer region bind T4 with negative cooperativity. Under physiological conditions, the bound between the natural ligand and the tetramer can’t be broken down. Moreover, there is only one hormone bound per tetramer. The negative cooperativity mechanism
Two hormone binding sites are located at the dimer–dimer region bind T4 with negative cooperativity. Under physiological conditions, the bound between the natural ligand and the tetramer can’t be broken down. Moreover, there is only one hormone bound per tetramer. The negative cooperativity mechanism


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Abnormal TTR levels are found in neuropathologies such as Guillain-Barré syndrome (GBS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), amd Parkinson’s disease (PD)<ref name= "Vieira" />.
Abnormal TTR levels are found in neuropathologies such as Guillain-Barré syndrome (GBS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), amd Parkinson’s disease (PD)<ref name= "Vieira" />.
The most known defect related to TTR is the formation of amyloid fibrils, which can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)<ref> Faria TQ, Almeida ZL, Cruz PF, Jesus CS, Castanheira P, Brito RM. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015 Mar 4;17(11):7255-63. PMID:25694367 doi:http://dx.doi.org/10.1039/c4cp04549a </ref>. Another type of disease possibly engendered due to TTR amyloid fibrils is the central nervous system selective amyloidosis (CNSA) including familial oculoleptomeningeal amyloidosis characterized by an eye injury, or meningocerebrovascular amyloidosis if the eye is not affected. <ref> P.Gambetti, C. Russo. Human brain amyloidoses. Neuphrol Dial Transplant. 1998; 13 [Suppl 7] : 33-40</ref>
Additionally, there is another defect related to TTR, which is more probable and known: the formation of amyloid fibrils. It can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)<ref> Faria TQ, Almeida ZL, Cruz PF, Jesus CS, Castanheira P, Brito RM. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015 Mar 4;17(11):7255-63. PMID 25694367 doi:http://dx.doi.org/10.1039/c4cp04549a </ref>. Another type of disease possibly engendered due to TTR amyloid fibrils is the central nervous system selective amyloidosis (CNSA) including familial oculoleptomeningeal amyloidosis characterized by an eye injury, or meningocerebrovascular amyloidosis if the eye is not affected. <ref> P.Gambetti, C. Russo. Human brain amyloidoses. Neuphrol Dial Transplant. 1998; 13 [Suppl 7] : 33-40</ref>
 


Inappropriate TTR foldings cause amyloidosis. Indeed, aggregates formation can be explained by a destabilization of the TTR’s native conformation, namely the tetramer dissociation into an alternative folded monomeric intermediate. The final result is a protein self-assembly. A particular beta-pleated-sheet structure characterizes the proteins with amyloidogenic potential. <ref name="Klabunde" />
Inappropriate TTR foldings cause amyloidosis. Indeed, aggregates formation can be explained by a destabilization of the TTR’s native conformation, namely the tetramer dissociation into an alternative folded monomeric intermediate. The final result is a protein self-assembly. A particular beta-pleated-sheet structure characterizes the proteins with amyloidogenic potential. <ref name="Klabunde" />
TTR aggregation into amyloid fibrils leads to insolubility. Consequently, it creates abnormal deposits in the peripheral nerves in the case of FAP, in the central nerves for CNSA, and in heart tissues for FAC and SSA. Therefore, the insoluble proteins alter the corresponding organ and tissue functions, and are unable to be subjected to a proper degradation by cell metabolism.
TTR aggregation into amyloid fibrils leads to insolubility. Consequently, it creates abnormal deposits in the peripheral nerves in the case of FAP, in the central nerves for CNSA, and in heart tissues for FAC and SSA. Therefore, the insoluble proteins alter the corresponding organ and tissue functions, and are unable to be subjected to a proper degradation by cell metabolism.


In most of the cases, autosomal dominant mutations of the TTR gene are at the origin of the Human familial amyloidosis (FAP, FAC, CNSA) through TTR conformational disorder. Val30Met is the most recensed amyloidogenic point mutation observed ([[4tl4]]). However, SSA differentiates from these TTR-related hereditary amyloidosis by usually affecting patients in advanced age, as it involves an aggregate formation due to a progressive accumulation of wild-type TTR proteins mainly associated to misshaping and beta-strand lacking <ref> Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P, Wechalekar A, Gibbs SD, Venner CP, Wassef N, McCarthy CA, Gilbertson JA, Rowczenio D, Hawkins PN, Gillmore JD, Lachmann HJ (April 2013). "Senile systemic amyloidosis: clinical features at presentation and outcome". Journal of the American Heart Association. 2 (2): e000098. PMC 3647259. PMID 23608605 doi: http://dx.doi.org/10.1161/JAHA.113.000098 </ref><ref> Gustavsson A. Jahr H, Tobiassen R, Jacobson DR, Sletten K, Westermark P. Amyloid fibril composition and transthyretin gene structure in senile systemic amyloidosis. 1995 Nov; 73(5):703-8 </ref>
In most of the cases, autosomal dominant mutations of the TTR gene are at the origin of the Human familial amyloidosis (FAP, FAC, CNSA) through TTR conformational disorder. Val30Met is the most recensed amyloidogenic point mutation observed ([[4tl4]]). However, SSA differentiates from these TTR-related hereditary amyloidosis by usually affecting patients in advanced age, as it involves an aggregate formation due to a progressive accumulation of wild-type TTR proteins mainly associated to misshaping and beta-strand lacking <ref> Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P, Wechalekar A, Gibbs SD, Venner CP, Wassef N, McCarthy CA, Gilbertson JA, Rowczenio D, Hawkins PN, Gillmore JD, Lachmann HJ (April 2013). "Senile systemic amyloidosis: clinical features at presentation and outcome". Journal of the American Heart Association. 2 (2): e000098. PMC 3647259. PMID 23608605 doi:http://dx.doi.org/10.1161/JAHA.113.000098 </ref><ref> Gustavsson A. Jahr H, Tobiassen R, Jacobson DR, Sletten K, Westermark P. Amyloid fibril composition and transthyretin gene structure in senile systemic amyloidosis. 1995 Nov; 73(5):703-8 </ref>




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=== Non-steroidal anti-inflammatory drugs===
=== Non-steroidal anti-inflammatory drugs===


[[Image: Drugstructure.png | thumb | left | alt=Puzzle globe| Structures of thyroxine (T4), the natural ligand of TTR and other designed TTR fibril formation inhibitors| 200 px]]
 
 
[[Image:nat_lig.jpg|thumb|left|alt=Puzzle globe|Caption for the image|Structures of thyroxine (T4), the natural ligand of TTR and other designed TTR fibril formation inhibitors|200px]]
 
 




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The fibril formation inhibitors studied are ligands that resemble to the natural ligand T4 but more efficient in binding TTR, leading to a decrease of the amyloidogenic potential. The first potent amyloid inhibitors developed were non-steroidal anti-inflammatory drugs (NSAID), such as flufenamic acid ([[1bm7]]), resveratrol ([[1dvs]]), diclofenac ([[1dvx]]), flurbiprofen ([[1dvt]]), indomethacin, diflunisal, meclofenamic acid, mefenamic acid, or fenoprofen.
The fibril formation inhibitors studied are ligands that resemble to the natural ligand T4 but more efficient in binding TTR, leading to a decrease of the amyloidogenic potential. The first potent amyloid inhibitors developed were non-steroidal anti-inflammatory drugs (NSAID), such as flufenamic acid ([[1bm7]]), resveratrol ([[1dvs]]), diclofenac ([[1dvx]]), flurbiprofen ([[1dvt]]), indomethacin, diflunisal, meclofenamic acid, mefenamic acid, or fenoprofen.
However, regardless of a noticeable decrease of the TTR’s amyloidogenic potential <ref name="Klabunde" />, prolonged NSAIDs administration could provoke renal failure, cardiac side effects, and gastrointestinal ulcers. <ref>Bally, M; Dendukuri, N; Rich, B; Nadeau, L; Helin-Salmivaara, A; Garbe, E; Brophy, JM (9 May 2017). "Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data". BMJ (Clinical Research Ed.). 357: j1909. PMC 5423546. PMID 28487435 doi: http://dx.doi.org/10.1136/bmj.j1909</ref> Gastric toxicity is linked to NSAID’s binding to a [[cyclooxygenase]] isoform, resulting in an inhibition of the activity of COX-1 and/or COX-2 associated to prostaglandin’s negative regulation. <ref name="Klabunde" />
However, regardless of a noticeable decrease of the TTR’s amyloidogenic potential <ref name="Klabunde" />, prolonged NSAIDs administration could provoke renal failure, cardiac side effects, and gastrointestinal ulcers. <ref>Bally, M; Dendukuri, N; Rich, B; Nadeau, L; Helin-Salmivaara, A; Garbe, E; Brophy, JM (9 May 2017). "Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data". BMJ (Clinical Research Ed.). 357: j1909. PMC 5423546. PMID 28487435 doi: http://dx.doi.org/10.1136/bmj.j1909</ref> Gastric toxicity is linked to NSAID’s binding to a [[cyclooxygenase]] isoform, resulting in an inhibition of the activity of COX-1 and/or COX-2 associated to prostaglandin’s negative regulation. <ref name="Klabunde" />




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