Transthyretin

Figure 14.7 Ribbon diagram of one subunit of the globular form of transthyretin. The p strands are labeled A to H from the amino end. Strands C and D are thought to be unfolded to produce the conformation that forms amyloid fibrils. (Adapted from C.C.F. Blake et al., /. Mol. Biol. 121 339-356, 1978.)...

Figure 14.8 Proposed model of p sheet helix of the fibrous form of transthyretin. The repeating unit of the P helix comprises 24 P strands with an average twist of 15° between each strand giving a complete turn of 360°. Four transthyretin polypeptide chains contribute to the repeat unit and are shown here in different colors. (Adapted from C. Blake and L. Serpell, Structure 4 989-998, 1996.)...

Blake, C., Serpell, L. Synchrotron x-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous P sheet helix. Structure 4 989-998, 1996. 

Occupancy of retinol binding site of transthyretin in vertebrate blood... 

Residues of PCBs in animal tissues include not only the original congeners themselves, but also hydroxy metabolites that bind to cellular proteins, for example, transthyretin (TTR Klasson-Wehler et al. 1992 Brouwer et al. 1990 Fans et al. 1993). Small residues are also found of methyl-sulfonyl metabolites of certain PCBs (Bakke et al. 1982, 1983). These appear to originate from the formation of glutathione conjugates of primary epoxide metabolites, thus providing further evidence of the existence of epoxide intermediates. Further biotransformation, including methylation, yields methyl-sulfonyl products that are relatively nonpolar and persistent. 

Some hydroxy metabolites of coplanar PCBs, such as 4-OH and 3,3 4,5 -tet-rachlorobiphenyl, act as antagonists of thyroxin (Chapter 6, Section 6.2.4). They have high affinity for the thyroxin-binding site on transthyretin (TTR) in plasma. Toxic effects include vitamin A deficiency. Biomarker assays for this toxic mechanism include percentage of thyroxin-binding sites to which rodenticide is bound, plasma levels of thyroxin, and plasma levels of vitamin A. 

Transthyretin (TTR) A protein complex found in blood that binds both retinol (vitamin A) and thyroxine. 

Darnerud, P.O., Morse, D.C., Klasson-Wehler, E. et al. (1996). Binding of 3,3, 4,4 TCB metabolite to fetal transthyretin and effects on fetal thyroid hormone levels in mice. Toxicology 106, 105-114. 

Lans, M.C., Klasson-Wehler, E., and Willemsen, M. et al. (1993). Structure-dependant competitive interaction of hydroxy-PCB, PCDD, and PCDE with transthyretin. Chemico-Biological Interactions 88, 7-21. 

Transthyretin (formerly prealbumin binds T4 and forms a complex with retinol-binding protein)... 

Chen, M.-L. Chen, C.-H. (2005a). Comparative proteome analysis revealed up-regulation of transthyretin in rat brain under chronic clozapine treatment. /. Psychiatric Res., 41(1/2), 63-8. 

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

Baures PW, Peterson SA, Kelly JW. Discovering transthyretin amyloid fibril inhibitors by limited screening. Bioorg Med Chem 1998 6 1389-1401. 

Peterson SA, Klabunde T, Lashuel HA, Purkey H, Sacchettini JC, Kelly JW. Inhibiting transthyretin conformation changes that lead to amyloid fibril formation. Proc Natl Acad Sci USA 1998 95 12956-12960. 

Oza VB, Petrassi HM, Purkey HE, Kelly JW. Synthesis and evaluation of anthranilic acid-based transthyretin amyloid fibril inhibitors. Bioorg Med Chem Lett 1999 9 1-6. 

Lashuel HA, Lai Z, Kelly JW. Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation implications for wild-type, V30M, and L55P amyloid fibril formation. Biochemistry 1998 37 17851-17864. 

Lai Z, Colon W, Kelly JW. The acid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-assemble into amyloid. Biochemistry 1996 35 6470-6482. 

Kelly JW, Colon W, Lai Z, Lashuel HA, McCulloch J, McCutchen SL, Miroy GJ, Peterson SA. Transthyretin quaternary and tertiary structural... 

Bonifacio MJ, Sakaki Y, Saraiva MJ. In vitro amyloid fibril formation from transthyretin the influence of ions and the amyloidogenicity of TTR variants. Biochim Biophys Acta 1996 1316 35 42. 

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