Serum transthyretin

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]. 

The failure of proteins to fold into their functional forms can occasionally lead to "misfolding" or "conformational" diseases.140 Many of these diseases are associated with the formation of amyloid protein, an insoluble material that is deposited as fibrils or plaques in different tissues and organs of the body. They include amyloid Ap protein as the major constituent of the plaques in Alzheimer patients, PrPc associated with neuro-degenerative diseases, a-synuclein (AS) associated with Parkinson s diseases, transthyretin (TTR) as a homotetrameric protein that is involved in the transport of thyroid hormones and retinol in human serum. In particular, the Ap protein is a peptide of 39-43 amino acids that is the... 

AP and tau, 6-2 microglobulin Immunoglobulin light chain Serum amyloid A (SAA) Transthyretin (TTR) Apolipoprotein A-l Cystatin A Gelsolin... 

Free retinol is released from the liver as a 1 1 complex of retinol with the 21-kDa retinol-binding protein.k l This protein is normally almost saturated with retinol and is bound to another serum protein, the 127-residue transthyretin (prealburnin).m/n Some of the retinol is oxidized to retinoic acid. 

PEM is frequently associated with changes in serum markers such as protein, lipid, and nitrogen (Hendrickse, 1991). Decreased serum albumin levels have been used as a standard PEM indicator. Since albumin has a long half-life of 18 days in the plasma and a large pool size that decreases in various illnesses (such as hepatic insufficiency and nephrosis), it is not a specific marker for recent nutritional inadequacies. Prealbumin (or transthyretin), by virtue of its higher catabolic rate (half-life = 1.9 days) and small pool size, is a very sensitive and fairly specific indicator of acute malnutrition and shortterm responses to nutritional replacements in patients of all ages (Bernstein and Ingenbleek, 2002). 

FIGURE 7 Deconvolved ESI mass spectrum of transthyretin obtained by immunoprecipitation from the serum of a patient found to have a novel form of ATTR A, wild-type TTR (mass 13,759.1) B, variant TTR (mass 13,786.5) C, sulfated TTR (mass 13,839.0) and D, sulfated variant TTR (mass 13,864.9). 

Theberge, R., Skinner, M., Connors, L., Skare, J., and Costello, C. E. (1999). Characterization of transthyretin mutants from serum using immunoprecipitation, HPLC/Electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry, Anal. Chem. 71, 452-459. 

Brouwer A and van den Berg KJ (1986) Binding of a metabolite of 3,4,3, 4 -tetra-chlorobiphenyl to transthyretin reduces serum vitamin A transport by inhibiting the formation of the protein complex carrying both retinol and thyroxin. Toxicology and Applied Pharmacology 85,301-12. 

Several of the proteins in Table 20-3 are acute phase reactants (APR) with the concentrations of tti-antitrypsin (AAT), aj-acid glycoprotein (AAG), haptoglobin (Hp), ceruloplasmin, C4, C3, procalcitonin (PCT), and serum amyloid A (SAA) increasing in most forms of inflammation these are called positive APR. Others, such as transthyretin... 

In clinical practice, only a few laboratory tests are of value in tlie assessment of protein-energy status It is particularly important to recognize that serum protein concentrations are not helpful in sick patients with any form of inflammatory process (see Chapter 20). Although serum albumin is often measured and reported as an indicator of protein-energy status, factors such as increased transcapillary escape and reduced hepatic synthesis malce it of little value as a nutritional marker. Serum albumin is, however, a valuable prognostic marker and is frequently used as part of prognostic indices. Short half-life proteins, such as transthyretin (prealbumin) also may be of some limited value in patients with no inflammatory response. 

LBM includes skeletal muscle, somatic protein, and functional proteins such as circulating proteins and the visceral proteins. Biochemically, LBM can be assessed by measuring the serum visceral proteins, albumin (ALB), transferrin (TFN), and prealbumin (thyroxine-binding prealbumin or transthyretin). Other serum proteins, such as retinol-binding protein, flbronectin (an opsonic protein), and somatomedin-C (insulin-like growth factor-1), that have a very short half-life (less than 12 to 24 hours), have been suggested as... 

Vitamin A homeostasis was altered in rats that were exposed to 100 mg/kg/day (only tested dose) of PCB 169 in the diet for 77 days (Bank et al. 1989). Effects included significantly decreased hepatic vitamin A, increased renal vitamin A, increased serum retinol, decreased plasma clearance and half-time of injected retinol (i.e., intravenously administered [ Hjretinol-labeled retinol binding protein-transthyretin complex), decreased hepatic and increased renal uptake uptake of injected retinol, and increased urinary and fecal excretion of injected retinol. 

PCBs, including poly-ort/jo-substituted PCBs, which have a very low affinity for the Ah receptor, inhibit the binding of T4 to transthyretin, an important transport protein for both T4 and T3 (Chauhan et al. 2000 Cheek et al. 1999 Darnerud et al. 1996a). Inhibition of binding of thyroid hormones to transthryetin could alter hormone delivery to target tissues, including the brain, and could also result in depressed levels of serum total TT4 or TT3 (Brouwer et al. 1998). 

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