Thyroxin-prealbumin binding

Figure 2. Cross Section of the Thyroxin-Prealbumin Binding Surface.

Thyroxine-binding globulin is the least abundant of the three major transport proteins. Nevertheless, it carries about 70% of the circulating T4 and Tj by virtue of its high affinity for the two hormones. Transthyretin, formerly known as thyroxine-binding prealbumin, binds only about 10 to 15% of the hormones. Albumin, a protein that has a binding affinity for a multitude of small molecules, has an even lower affinity for T4 and T3 than... 

Figure 28-21 Themoleculei-thyroxine. 7. binds to prealbumin, a protein found in blood. Based on x-ray data of the >-thyroxine-prealbumin complex, the binding affinity of novel analogues was prediaed by using a molecular modeling approach.

Figure 28-22 The experimental x-ray crystal structure of prealbumin with bound i-thyroxine. Prealbumin is a letramer with four identical subunits, A, B, C, and D, The four identical subunits form a channel with two bound i-thyroxine molecules. The binding sites have a C2 axis of symmetry.

Because of certain proprietary considerations, a protein other than the ALS enzyme will be used to demonstrate how molecular modeling techniques can be applied to the design of crop protection chemicals. Human serum prealbumin has been used by Blaney, et al (15) to model drug-receptor interactions. Its function is to transport the hormone thyroxin. The binding site for thyroxin will... 

Blake, C.C.F., et al. Structure of human plasma prealbumin at 2.5 A resolution. A preliminary report on the polypeptide chain conformation, quaternary structure and thyroxine binding. J. Mol. Biol. 88 1-12, 1974. 

Thyroxine (3, 5, 3,5-L-teraiodothyronine, T4) is a thyroid hormone, which is transformed in peripheral tissues by the enzyme 5 -monodeiodinase to triiodothyronine. T4 is 3-8 times less active than triiodothyronine. T4 circulates in plasma bound to plasma proteins (T4-binding globulin, T4-binding prealbumin and albumin). It is effective in its free non-protein-bound form, which accounts for less than 1%. Its half-life is about 190 h. 

Prealbumin (trans- thyretin) 2-3 Binds triiodothyronine and to a lesser extent thyroxine carrier for retinolbinding protein Kidney dysfunction Cirrhosis, hepatitis, stress, inflammation, surgery, hyperthyroidism, cystic fibrosis, kidney dysfunction, zinc deficiency... 

Amino Acid Systems Glutamine binding sites, 46, 414 labeling of the active site of r-aspartate /3-decarboxylase with yS-chloro-r-ala-nine, 46, 427 active site of r-asparaginase reaction with diazo-4-oxonorvaline, 46, 432 labeling of serum prealbumin with N-bro-moacetyl-L-thyroxine, 46, 435 a pyridoxamine phosphate derivative, 46, 441. 

Thyroxine binding prealbumin (TBPA) carries about 30% T but no Tj. Its affinity is only of the order of 10 M, but it is much more abundant in semm than is TBG. The amino acid sequence and the structure of this protein are known. Four identical subunits (127 amino acids each) form a prolate ellipsoid. Noncovalent interactions between the subunits form a channel of I nm diameter along the long axis, which has a funnel-shaped opening of 2.5 nm. The T molecule is held in one arm of this channel, binding... 

McKinney JD, Chae K, Oatley SJ, et al. 1985a. Molecular interactions of toxic chlorinated dibenzo-p-dioxins and dibenzofurans with thyroxine binding prealbumin. J Med Chem 28 375-381. 

J. D. McKinney, K. Chae, S. J. Oatley, and C. C. F. Blake, /. Med. Chem., 28, 375 (1985). Molecular Interactions of Toxic Chlorinated Dibenzo-p-dioxins and Dibenzofurans with Thyroxine Binding Prealbumin. 

RBP forms a 1 1 complex with the tetrameric thyroxine-binding prealbumin, transthyretin. This is important to prevent urinary loss of retinol bound to the relatively small RBP (Mr 21,000), which would be filtered by the glomerulus transthyretin has an Mr of 54,000 hence, the complex will not normally be filtered, ffowever, moderate renal damage, or the increased permeability of the glomerulus in infection, may result in considerable loss of vitamin A bound to RBP-transthyretin. 

Numerous transport proteins, including prealbumin (= transthyretin), albumin (72), ceruloplasmin, haemo-pexin, haptoglobin, retinol-binding globulin, thyroxine-... 

The concentration of free rather than bound thyroxine is considered to be the most accurate assessment of thyroid activity as this is the fraction which can penetrate cell membranes and exert a metabolic effect. Free thyroxine exists in equilibrium with thyroxine bound to globulin, albumin, and prealbumin. Any changes in the concentration of thyroid binding proteins leading to an increase in free hormone. Thyroid binding prealbumin is reduced after all kinds of stress and the reduction is significant within 24 hours. 

Kelleher, P. C., Phinney, S. D., Sims, E. A., Bogardus, C., Hortan, E. S., Bistrian, B. R., Ama-truda, J. M., and Lockwood, D. H. (1983). Effects of carbohydrate-containing and carbohydrate-restricted h3rpocaloric and eucaloric diets on serum concentrations of retinol-binding protein, thyroxine-binding prealbumin, and transferrin. Metabolism 32, 95-101. 

Figure 28-23 Using molecular modeling methods, four I -thyroxine analogues were predicted to have good binding affinity (8 > 9 = 10 > 11) to prealbumin.

Figure 10. Model of thyroxine binding prealbumin-receptor interaction based on crystallographic protein data (39)...

Plasma cortisol concentration is increased because of decreased metabolic clearance. The plasma concentrations of total triiodothyronine T3), thyroxine (T4), and TSH are considerably reduced, with the thyroxine concentration being most affected. This is partly due to reduced concentrations of thyroxine-binding globulin and prealbumin. 

Transthyretin (prealbumin) and retinol-binding protein (RBP) are transport proteins that migrate together as a 1 1 molecular complex. Transthyretin was originally named prealbumin because of its electrophoretic mobility it was renamed in 1981 to reflect its binding and transport of both thyroid hormones (thyroxine and triiodothyronine) and RBP. 

Transthyretin amyloidosis (also called familial amyloid polyneuropathy) is an autosomal dominant syndrome characterized by peripheral neuropathy. This disease results from one of five mutations identified thus far in the gene for transthyretin. Transthyretin is also called prealbumin (although it has no structural relationship to albumin) because it migrates ahead of albumin in standard electrophoresis at pH 8.6. Transthyretin is synthesized in the liver and is a normal plasma protein with a concentration of 20-40 mg/dL. It transports thyroxine and retinol binding protein (Chapter 38). The concentration of transthyretin is significantly decreased in malnutrition and plasma levels are diagnostic of disorders of malnutrition (Chapter 17). 

Transthyretin (also known as prealbumin) Liver plasma circulating form is a tetramer composed of four identical monomers. M.W. 55,000 1-2 days N 20-40 mg/dl Mild 10-15 mg/dl Moderate 5-10 mg/dl Severe <5 mg/dl Circulates in plasma in a 1 1 complex with retinol-binding protein, transports thyroxine, has a small body pool, and has a short half-life. Sensitive indicator of protein deficiency and in the improvement with protein refeeding. 

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