Cystic fibrosis binding

Figure 41-17. Diagram of the structure of the CFTR protein (not to scale). The protein contains twelve transmembrane segments (probably helical), two nucleotide-binding folds or domains (NBFl and NBF2), and one regulatory (R) domain. NBFl and NBF2 probably bind ATP and couple its hydrolysis to transport of Cl . Phe 508, the major locus of mutations in cystic fibrosis, is located in NBFl.

Human leukocyte elastase is a protease that degrades elastin and other connective tissue components. It is implicated in the pathogenesis of pulmonary emphysema and other inflammatory diseases such as rheumatoid arthritis and cystic fibrosis. Porcine pancreatic elastase has often been used as a model for HLE. Both enzymes have a small primary binding site Si. 

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... 

Hyde, S.C., Emsley, P., Hartshorn, M.J., Mimmack, M.M., Gileadi, U., Pearce, S. R., Gallagher, M.P., Gill, D.R., Hubbard, R.E. and Higgins, C.F. (1990) Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature, 346, 362-365. 

Schwiebert, E. M., N. Kizer, D. C. Gruenert, and B. A. Stanton. 1992. GTP-binding proteins inhibit cAMP activation of chloride channels in cystic fibrosis airway epithelial cells. Proc Natl Acad Sci USA 89(22) 10623-7. 

Krivan, H. C., Ginsburg, V., and Roberts, D. D. (1988). Pseudomonas aeroginosa and Pseudomonas cepacia isolated from cystic fibrosis patients bind specifically to gangliotetraosyl-ceramide (asialo GMl) and gangliotriaosylceramide (asialo GM2). Arch. Biochem. Biophys. 260, 493-496. 

Pharmacokinetics Rapid, complete absorption after IM administration. Protein binding 0%-10%. Widely distributed (doesn t cross the blood-brain barrier, low concentrations in CSF). Excreted unchanged in urine. Removed by hemodialysis. Half-life 2-4 hr (increased in impaired renal function decreased in cystic fibrosis and burn or febrile patients). 

The ABC1 protein is a member of a large family of multidrug transporters, sometimes called ABC transporters because they all have ATP-binding cassettes they also have two transmembrane domains with six transmembrane helices (Chapter 11). These proteins actively transport a variety of ions, amino acids, vitamins, steroid hormones, and bile salts across plasma membranes. The CFTR protein that is defective in cystic fibrosis (see Box 11-3) is another member of this ABC family of multidrug transporters. 

Renal diseases such as uremia may result in decreased renal clearance of certain drugs.13 Gastrointestinal diseases, such as Crohn s disease, result in increased plasma protein binding of several drugs due to increased levels of binding proteins. Further, respiratory diseases such as cystic fibrosis increase the renal clearance of some drugs. 

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