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Transthyretin, or TTR for amyloidosis

THURSDAY Aug. 29, 2013 — A new medication appears to be highly effective in combating a heredity-based form of the organ-damaging genetic disorder known as amyloidosis, according to researchers.

Amyloidosis refers to a family of more than a dozen diseases in which different types of abnormal proteins called amyloids lodge in major organs and nerves. These amyloids build up to the point that they cause damage and, ultimately, organ failure.

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Transthyretin (TTR) is a serum and cerebrospinal fluid carrier of the thyroid hormone thyroxine (T4) and retinol-binding protein bound to retinol. This is how transthyretin gained its name, transports thyroxine and retinol. The liver secretes transthyretin into the blood, and the choroid plexus secretes TTR into thecerebrospinal fluid.

TTR was originally called prealbumin^[1] (or thyroxine-binding prealbumin) because it ran faster than albumin on electrophoresis gels.

Binding affinities

It functions in concert with two other thyroid hormone-binding proteins in the serum:

In cerebrospinal fluid TTR is the primary carrier of T4. TTR also acts as a carrier ofretinol (vitamin A) through its association with retinol-binding protein (RBP) in the blood and the CSF. Less than 1% of TTR’s T4 binding sites are occupied in blood, which is taken advantage of below to prevent TTRs dissociation, misfolding and aggregation which leads to the degeneration of post-mitotic tissue.

Numerous other small molecules are known to bind in the thyroxine binding sites, including many natural products (such as resveratrol), drugs (Tafamidis,^[2] or Vyndaqel, diflunisal,^[3][4][5] flufenamic acid),^[6] and toxins (PCB^[7]).

Structure

TTR is a 55kDa homotetramer with a dimer of dimers quaternary structure that is synthesized in the liver, choroid plexus and retinal pigment epithelium for secretion into the bloodstream, cerebrospinal fluid and the eye, respectively. Each monomer is a 127-residue polypeptide rich in beta sheet structure. Association of two monomers via their edge beta-strands forms an extended beta sandwich. Further association of two of these dimers in a face-to-face fashion produces the homotetrameric structure and creates the two thyroxine binding sites per tetramer. This dimer-dimer interface, comprising the two T4 binding sites, is the weaker dimer-dimer interface and is the one the comes apart first in the process of tetramer dissociation.^[8]

1.  Prealbumin at the US National Library of Medicine Medical Subject Headings (MeSH)
2. ^ ^a b Razavi H, Palaninathan SK, Powers ET, Wiseman RL, Purkey HE, Mohamedmohaideen NN, Deechongkit S, Chiang KP, Dendle MT, Sacchettini JC, Kelly JW (June 2003). “Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action”. Angew. Chem. Int. Ed. Engl. 42 (24): 2758–61.doi:10.1002/anie.200351179. PMID 12820260.
3. ^ Sekijima Y, Dendle MA, Kelly JW (December 2006). “Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis”. Amyloid 13 (4): 236–49. doi:10.1080/13506120600960882.PMID 17107884.
4. ^ Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW (January 2004). “Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis”. J. Med. Chem. 47 (2): 355–74. doi:10.1021/jm030347n.PMID 14711308.
5. ^ Vilaro M, Arsequell G, Valencia G, Ballesteros A, Barluenga J, Nieto J, Planas A, Almeida R, Saraiva MJ (2007). “Reengineering TTR amyloid inhibition properties of diflunisal”. In Seldin DC, Skinner M, Berk JL, Connors LH. XIth International Symposium on Amyloidosis. Boca Raton: CRC.doi:10.1201/9781420043358.ch69. ISBN 1-4200-4281-5.
6. ^ Baures PW, Oza VB, Peterson SA, Kelly JW (July 1999). “Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the non-steroidal anti-inflammatory drug, flufenamic acid”. Bioorg. Med. Chem. 7 (7): 1339–47.doi:10.1016/S0968-0896(99)00066-8. PMID 10465408.
7. ^ Purkey HE, Palaninathan SK, Kent KC, Smith C, Safe SH, Sacchettini JC, Kelly JW (December 2004). “Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity”.Chem. Biol. 11 (12): 1719–28.doi:10.1016/j.chembiol.2004.10.009. PMID 15610856.
8. ^ Foss TR, Wiseman RL, Kelly JW (November 2005). “The pathway by which the tetrameric protein transthyretin dissociates”. Biochemistry 44 (47): 15525–33.doi:10.1021/bi051608t. PMID 16300401.