Cell cycle enzyme formation

The progression of the cell cycle is regulated by interconversion processes, in each phase, special Ser/Thr-specific protein kinases are formed, which are known as cyclin-depen-dent kinases (CDKs). This term is used because they have to bind an activator protein (cyclin) in order to become active. At each control point in the cycle, specific CDKs associate with equally phase-specific cyclins. if there are no problems (e.g., DNA damage), the CDK-cyclin complex is activated by phosphorylation and/or dephosphorylation. The activated complex in turn phosphorylates transcription factors, which finally lead to the formation of the proteins that are required in the cell cycle phase concerned (enzymes, cytoskeleton components, other CDKs, and cyclins). The activity of the CDK-cyclin complex is then terminated again by proteolytic cyclin degradation. 

In many enzyme fermentations, the limiting component, usually the C-source, has to be added semi-continuously to keep its concentration at a predetermined, usually low, value. This measure makes it possible either to influence selectivity between different pathways or to uncouple predominantly cell growth during the first phase of the fermentation from predominantly product (i.e., enzyme) formation in the later stages of the fermentation cycle. Often, protein formation is induced by adding an inducer (see Chapter 4). During the fed-batch phase, the broth volume increases. Either the broth is harvested when the maximum volume is reached, or broth is withdrawn from time to time. The product is present in high concentrations. 

Sirohmus is a macrocychc lactone produced by the bacteria Streptomyces hygroscopious. Like the calcineurin inhibitors cyclosporine and tacrolimus its mechanism of action involves formation of a complex with an immunophiUn, in this case, FKBP-12. Unlike cyclosporine and tacrolimus, sirohmus does not affect calcineurin activity but binds to and inhibits the mammalian kinase, target of rapamycin (mTOR.). mTOR is a key enzyme in cell-cycle progression. When inhibited this kinase blocks cell cycle progression at the G1 to S phase transition (Dumont and Su, 1996 Sehgal, 2003). 

The alkoxyacid metabolites appear to be responsible for the toxic effects reported in the testes, bone marrow, and embryo. The testes, bone marrow, and embryo contain large numbers of rapidly dividing and differentiating cells, and it is possible that one or more processes of cell division and differentiation are affected. It has been hypothesized that alkoxyacetic acids may be introduced into the Krebs cycle by formation of methoxy- or ethoxyacetyl-CoA and by formation of methoxy- or ethoxycitrate by mitochondrial enzymes. 

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