Mobile defects in proteins

Vitamin D is obtained in the diet or by photolysis of 7-dehydrocholesterol in skin exposed to sunlight. Calcitriol works in concert with parathyroid hormone in Ca2+ homeostasis, regulating [Ca2+] in the blood and the balance between Ca2+ deposition and Ca2+ mobilization from bone. Acting through nuclear receptors, calcitriol activates the synthesis of an intestinal Ca2+-binding protein essential for uptake of dietary Ca2+. Inadequate dietary vitamin D or defects in the biosynthesis of calcitriol result in serious diseases such as rickets, in which bones are weak and malformed (see Fig. 10-20b). 

A classic example of essential metal deficiency resulting from nonessential metal exposure is Itai itai disease. Cadmium pollution in the Jinzu River basin in Japan resulted in severe nephrotoxicity in approximately 184 people. Renal tubule damage caused excessive loss of electrolytes and small proteins from the urine. In severe cases, urinary Ca loss was so severe that bone Ca was mobilized, resulting in osteomalacia. Renal tubular defects persisted for life and induced hypophosphatemia, hyperuricemia, and hyperchloremia, which are characteristic biochemical features of Itai-itai disease (see Section 21.6.1). 

Ligands by themselves are often effective drugs or detoxificants. For example, D-penicil-lamine (3, a substituted cysteine) is used to mobilize copper deposited in reducing tissues in patients with Wilson s disease (hepatolenticular degeneration), a hereditary defect in copper metabolism. The copper transport protein (ceruloplasmin) of blood plasma is faulty and bonds copper ions less effectively than it should. The enantiomeric L-penicillamine is ineffective as a treatment. If (as may happen) D-penicillamine is either inactive or gives rise to intense nausea, triethylenetetraamine (trien 4) is often used. 

Ihara et al. (1983), working with PRV, found that it differs from HSV-1 in that only one immediate-early polypeptide, with an electrophoretic mobility similar to that of ICP4 of HSV, was made after reversing a cycloheximide block. Cellular protein synthesis was inhibited soon after reversal. is a mutant of PRV with a defect in the immediate-early protein which (like tsK of HSV-1 see Section 7.6) is unable to progress from immediate-early to early protein synthesis at the nonpermissive temperature (41°C). This mutant caused significant shut-off of cellular protein and DNA synthesis at 41°C but less than wild-type virus. It was concluded that the immediate-early protein is involved in the shut-off, but either the mutant form is partially defective in this function or some later viral proteins also contribute to the shut-off by wild-type virus. The case for the host-suppressing function of the immediate-early protein would be strengthened if it were confirmed that shut-off occurred after reversal of cycloheximide in the presence of actinomycin, as was reported for polysome breakdown (Ben-Porat et al., 1971). 

Studies of the effect of permeant s size on the translational diffusion in membranes suggest that a free-volume model is appropriate for the description of diffusion processes in the bilayers [93]. The dynamic motion of the chains of the membrane lipids and proteins may result in the formation of transient pockets of free volume or cavities into which a permeant molecule can enter. Diffusion occurs when a permeant jumps from a donor to an acceptor cavity. Results from recent molecular dynamics simulations suggest that the free volume transport mechanism is more likely to be operative in the core of the bilayer [84]. In the more ordered region of the bilayer, a kink shift diffusion mechanism is more likely to occur [84,94]. Kinks may be pictured as dynamic structural defects representing small, mobile free volumes in the hydrocarbon phase of the membrane, i.e., conformational kink g tg ) isomers of the hydrocarbon chains resulting from thermal motion [52] (Fig. 8). Small molecules can enter the small free volumes of the kinks and migrate across the membrane together with the kinks. 

The chemical and physical stability of a solid drug decreases with decreasing crystallinity and increasing amorphous character, corresponding to an increase in molecular mobility (i.e., diffusivity) in the solid state. This phenomenon is of particular significance to proteins, peptides, and other biological materials. Certain additives other than water may stabilize proteins in the solid state, perhaps by locking in the defects. 

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