Chemical genetics limitations

In eukaryotes, translation initiation is rate-limiting with much regulation exerted at the ribosome recruitment and ternary complex (elF2 GTP Met-tRNAjMet) formation steps. Although small molecule inhibitors have been extremely useful for chemically dissecting translation, there is a dearth of compounds available to study the initiation phase in vitro and in vivo. In this chapter, we describe reverse and forward chemical genetic screens developed to identify new inhibitors of translation. The ability to manipulate cell extracts biochemically, and to compare the activity of small molecules on translation of mRNA templates that differ in their factor requirements for ribosome recruitment, facilitates identification of the relevant target. 

A biomarker of susceptibility can be defined as "an indicator of an inherent or acquired limitation of an organism to respond to the challenge of exposure to a specific xenobiotic substance" [4]. These markers indicate differences in individuals or populations that affect the body s response to xenobiotic exposure. They may include variations in the balance between enzymes that detoxify or enhance the toxicity of chemicals, genetic differences in the capacity of cells to recover from injury, inherited genetic defects that increase the risk of cancer. 

To conduct a chemical genetic phenotypic screen there is an absolute requirement for a large selection of bioactive molecules. The primary limits on these molecules availability are the synthetic routes to them. For this reason there are three main classes of such compounds natural products, synthetic peptides and pharmaceutical-like molecules. 

In summary, chemical genetics facilitates a real-time control in cellular studies and only diffusion could be a limitation. 

As forward chemical genetic screens are commonly performed in the context of a human disease hypothesis, a blurred line between probe development and drug discovery can potentially create incentives to limit the use of discovered compounds through patent protection. While the intent of chemical biology is not to stifle therapeutic development but conversely to enable future... 

Significant differences in net photosynthetic assimilation of carbon dioxide are apparent between C, C, and CAM biomass species. One of the principal reasons for the generally lower yields of C biomass is its higher rate of photorespiration if the photorespiration rate could be reduced, the net yield of biomass would increase. Considerable research is in progress (ca 1992) to achieve this rate reduction by chemical and genetic methods, but as yet, only limited yield improvements have been made. Such an achievement with C biomass would be expected to be very beneficial for foodstuff production and biomass energy appHcations. 

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