Phosphatase synthesis

Vitamin D also exerts an effect upon the intestinal absorption of phosphorus probably in relation with the stimulation of alkaline phosphatase synthesis [22,35],... 

Fig. 11. Partial obstruction of the bile passages (as in patients with cholan olar carcinoma or hepatic metastases) enhances alkaline phosphatase synthesis proximal to the site of obstruction. Such patients may have normal serum bilirubin values because the excretory processes in other parts of the liver are unimpaired.

The relatively recalcitrant dissolved poly-phenolic compounds resulting from breakdown of higher plants (fulvic and humic acids) complex with many bacterial and algal enzymes, but particularly phosphatases (Wetzel, 1992). The formation of such complexes inactivates phosphomonoesterase (Boavida and Wetzel, 1998), which is inhibited both competitively and non-competitively (Wetzel, 1992). Phosphorus-limited cells therefore need to expend more energy on phosphatase synthesis, and enhanced phosphomonoesterase activity has been reported for waters with increased humic materials (Stewart and Wetzel, 1992b). Wetzel (1992) pointed out these results with frequent observations (e.g. Jones, 1990) that the primary production in humic-rich waters is consistently lower than in clear waters with comparable loadings and light availability. 

The glucocorticoid induction of HeLa cell alkaline phosphatase requires concomitant protein synthesis [100], but immunoprecipitation and radioimmunoprecipitation studies strongly suggest that the quantities of alkaline phosphatase antigen and its rate of synthesis are not altered by the steroid inducer [101]. Physical and biochemical differences have been observed between the uninduced or basal enzyme and the induced form [101]. Thus, the induction does not seem to be due to an increased rate of de novo phosphatase synthesis but more likely is due to the conversion of an antigenic precursor to a catalytically active (or more active) molecule. The conversion process apparently is inhibited... 

The regulation of alkaline phosphatase synthesis in E. coli involves the elaboration of a proteic substance referred to as the R2A protein. The presence of the R2A protein is determined genetically and is repressed by inorganic phosphate. Galactoside elaboration is in part regulated by a protein substance. 

This protein was identified by electrophoretic analysis of the protein composition of different E. coli mutants, some of which were very active with respect to the inducible synthesis of alkaline phosphatase (up to 6% of their dry weight) while others were active with respect to constitutive phosphatase synthesis (deletion of the regulator gene). Mutation of the regulator gene locus led to changes in the electrophoretic and immunochemical properties of this protein. 

Cyclosporine A (CsA) is a water-insoluble cyclic peptide from a fungus composed of 11 amino acids. CsA binds to its cytosolic receptor cyclophilin. The CsA/cyclophilin complex reduces the activity of the protein phosphatase calcineurin. Inhibition of this enzyme activity interrupts antigen receptor-induced activation and translocation of the transcription factor NEAT to the nucleus which is essential for the induction of cytokine synthesis in T-lymphocytes. 

After their synthesis (translation), most proteins go through a maturation process, called post-translational modification that affects their activity. One common post-translational modification of proteins is phosphorylation. Two functional classes of enzymes mediate this reversible process protein kinases add phosphate groups to hydroxyl groups of serine, threonine and tyrosine in their substrate, while protein phosphatases remove phosphate groups. The phosphate-linking... 

An illustrative example of an alternative strategy (cf Fig. 11c) involving the use of a novel traceless linker is found in the multistep synthesis of 6-epi-dysidiolide (363) and several dysidiolide-derived phosphatase inhibitors by Waldmann and coworkers [153], outlined in Scheme 70. During the synthesis, the growing skeleton of 363 remained attached to a robust dienic linker. After completion of intermediate 362, the terminal olefin in 363 was liberated from the solid support by the final metathesis process with concomitant formation of a polymer-bound cyclopentene 364. Notably, during the synthesis it turned out that polymer-bound intermediate 365a, in contrast to soluble benzoate 365b, produced diene 367 only in low yield. After introduction of an additional linker (cf intermediate 366), diene 367 was released in distinctly improved yield by RCM. 

In contrast, another group35 found that extracts of E. coli contained a mixture of pentulose phosphates at a concentration near 0.3 nmol per mg of the dry weight of cells. The sugars were estimated by gas chromatography-mass spectrometry after treatment of the extract with phosphatase followed by silylation, or borohydride reduction and acetylation. Furthermore, a partially purified preparation from these extracts catalyzed the synthesis of 1-deoxypentulose... 

Furthermore, the GPO procedure can also be used for a preparative synthesis of the corresponding phosphorothioate (37), phosphoramidate (38), and methylene phosphonate (39) analogs of (25) (Figure 10.20) from suitable diol precursors [106] to be used as aldolase substrates [102]. In fact, such isosteric replacements of the phosphate ester oxygen were found to be tolerable by a number of class I and class II aldolases, and only some specific enzymes failed to accept the less polar phosphonate (39) [107]. Thus, sugar phosphonates (e.g. (71)/(72)) that mimic metabolic intermediates but are hydrolytically stable to phosphatase degradation can be rapidly synthesized (Figure 10.28). 

A. M. V. Garzillo, L. Badalucco, F. De Cesare, S. Grego, and V. Buonocore, Synthesis and characterization of an acid phosphatase-polyresorcinol complex. Soil Biol. Biochem 2S 1155 (1996). 

Cyclosporine and tacrolimus belong to a class of immunosuppressants called the calcineurin inhibitors. These agents are considered by many to be the cornerstone of medical immunosuppression. The calcineurin inhibitors work by complexingwith cytoplasmic proteins (cyclosporine with cyclophylin and tacrolimus with FK binding protein 12). These complexes then inhibit calcineurin phosphatase, which results in reduced IL-2 gene transcription. The final outcome is a decrease in IL-2 synthesis and a subsequent reduction in T cell activation.7 11 20 21... 

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