Decreased affinity

FIG. 16-30 Operational steps in displacement chromatography, The column, initially equilibrated with a carrier solvent at time 0, is loaded with feed until time tp and supplied with displacer for a time to + tp. Development of the displacement train occurs during the time to and elution of the separated products ends at time tp. tp is the time required to remove the displacer from the column and restore the initial conditions, Components are niimhered in order of decreasing affinity for the stationary phase, [Reference Horoath et at, J, Ghromatogr, 2i8, 365 (1981). Reprinted with peimission of], Ghromatogr,]... 

TABLE 16-15 Concentrations and h-Function Roots for Displacement Chromatography of a Mixture of M-1 Components Numbered in Order of Decreasing Affinity for the Stationary Phase (Adapted from Frenz and Horvath/ 1985). 

Of course the interaction between water molecules and the hydration sites depends on their chemical nature. According to the results of IR-measurements the following order of decreasing affinity was given by Falk et al.160) and was accepted as being quite reasonable 161) ... 

Allosteric modulators that block receptor function produce insurmountable antagonism. In addition, modulators that block function also can alter (increase or decrease) affinity. 

Overproduction of the chromosomal genes for the dihydrofolate reductase (DHFR) and the dihydroptero-ate synthase (DHPS) leads to a decreased susceptibility to trimethoprim and sulfamethoxazol, respectively. This is thought to be the effect of titrating out the antibiotics. However, clinically significant resistance is always associated with amino acid changes within the target enzymes leading to a decreased affinity of the antibiotics. 

Decreased affinity of target / -Lactam antibiotics Altered PBPst... 

Malloy PJ, Eccleshall TR, Gross C, Van Maldergem L, Bouillon R, Feldman D. Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness. J Clin Invest 1997 99[2] 297-304. 

For constant-separation factor systems, the /(-I rails formal ion of Helfferich and Klein (gen. refs.) or the method of Rhee et al. [AlChE J., 28, 423 (1982)] can be used [see also Helfferich, Chem. Eng. Sci., 46, 3320 (1991)]. The equations that follow are adapted from Frenz and Horvath [AlChE ]., 31, 400 (1985)] and are based on the h I ransiomialion. They refer to the separation of a mixture of M — 1 components with a displacer (component 1) that is more strongly adsorbed than any of the feed solutes. The multicomponent Langmuir isotherm [Eq. (16-39)] is assumed valid with equal monolayer capacities, and components are ranked numerically in order of decreasing affinity for the stationary phase (i.e., Ki > K2 > Km). 

PDE1 is phosphorylated by Ca27calmodulin-dependent protein kinase II (CaM-kinase II), which results in decreased affinity of this enzyme for Ca2+/calmodulin and an increase in the concentration of Ca2+ needed for its activation. PDE1 is also phosphorylated by protein kinase A, which likewise decreases its binding to Ca27calmodulin. 

In the case of /3-lactam antibiotics, the bacterial targets are the so-called PBPs. Modification of PBPs can result in a decreased affinity for /1-lactam antibiotics. In some cases the normal PBPs, through mutation, become less susceptible to acylation and inactivation by /3-lactam antibiotics. So, the target protein is unable to bind the antibiotic effectively, and hence resistance to a particular antibiotic is acquired [5]. Frequently, this difference consists of substitution of a single amino acid in the protein chain. In S. aureus, ac-... 

Figure 1. Hypothetical conformations of chain molecules (16) adsorbed on solid-liquid interfaces (a) lying on surface (b) standing on end, (c) looping, (d) coiled, (e) flat multilayer. a,c,d single chains adsorbed with decreasing affinity b,e, condensed surface layers.

Left shift (increased affinity for 02) Right shift (decreased affinity for 02)... 

Methotrexate is a folic acid analogue. Its mechanism of action is based on the inhibition of dihydrofolate reductase. Inhibition of dihydrofolate reductase leads to depletion of the tetrahydrofolate cofactors that are required for the synthesis of purines and thymidylate (see Fig. 2). Enzymes that are required for purine and thymidylate synthesis are also directly inhibited by the polyglutamates of methotrexate which accumulate with dihydrofolate reductase inhibition. The mechanisms that can cause resistance include decreased transport of methotrexate into the tumor cells, a decreased affinity of the antifolate for dihydrofolate reductase, increased concentrations of intracellular dihydrofolate reductase and decreased thymidylate synthetase activity. 

Chloramphenicol (Chloromycetin) is a nitrobenzene derivative that affects protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. It prevents the attachment of the amino acid end of aminoacyl-tRNA to the A site, hence the association of peptidyltransferase with the amino acid substrate. Resistance due to changes in the ribosomebinding site results in a decreased affinity for the drug, decreased permeability, and plasmids that code for enzymes that degrade the antibiotic. 

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